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Bertram JF, Cullen-McEwen LA, Andrade-Oliveira V, Câmara NOS. The intelligent podocyte: sensing and responding to a complex microenvironment. Nat Rev Nephrol 2025:10.1038/s41581-025-00965-y. [PMID: 40341763 DOI: 10.1038/s41581-025-00965-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/22/2025] [Indexed: 05/11/2025]
Abstract
Podocytes are key components of the glomerular filtration barrier - a specialized structure that is responsible for the filtration of blood by the kidneys. They therefore exist in a unique microenvironment exposed to mechanical force and the myriad molecules that cross the filtration barrier. To survive and thrive, podocytes must continually sense and respond to their ever-changing microenvironment. Sensing is achieved by interactions with the surrounding extracellular matrix and neighbouring cells, through a variety of pathways, to sense changes in environmental factors such as nutrient levels including glucose and lipids, oxygen levels, pH and pressure. The response mechanisms similarly involve a range of processes, including signalling pathways and the actions of specific organelles that initiate and regulate appropriate responses, including alterations in cell metabolism, immune regulation and changes in podocyte structure and cognate functions. These functions ultimately affect glomerular and kidney health. Imbalances in these processes can lead to inflammation, podocyte loss and glomerular disease.
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Affiliation(s)
- John F Bertram
- Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
- Australian Research Council Training Centre for Cell and Tissue Engineering Technologies, Brisbane, Queensland, Australia
| | - Luise A Cullen-McEwen
- Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Vinicius Andrade-Oliveira
- Center for Natural and Human Sciences, Federal University of ABC, Sao Paulo, Brazil.
- Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
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Mann N, Sun H, Majmundar AJ. Mechanisms of podocyte injury in genetic kidney disease. Pediatr Nephrol 2025; 40:1523-1538. [PMID: 39485497 PMCID: PMC11945604 DOI: 10.1007/s00467-024-06551-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 09/06/2024] [Accepted: 09/09/2024] [Indexed: 11/03/2024]
Abstract
Glomerular diseases are a leading cause of chronic kidney disease worldwide. Both acquired and hereditary glomerulopathies frequently share a common final disease mechanism: disruption of the glomerular filtration barrier, podocyte injury, and ultimately podocyte death and detachment. Over 70 monogenic causes of proteinuric kidney disease have been identified, and most of these genes are highly expressed in podocytes, regulating key processes such as maintenance of the slit diaphragm, regulation of actin cytoskeleton remodeling, and modulation of downstream transcriptional pathways. Collectively, these are increasingly being referred to as hereditary "podocytopathies," in which podocyte injury is the central feature driving proteinuria and kidney dysfunction. In this review, we provide an overview of the monogenic podocytopathies and discuss the molecular mechanisms by which single-gene defects lead to podocyte injury and ultimately glomerulosclerosis. We review how advances in genomic technology and a better understanding of the cell biological basis of disease have led to the development of more targeted and personalized therapeutic strategies, including an overview of small molecule and gene therapy approaches.
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Affiliation(s)
- Nina Mann
- Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
| | - Hua Sun
- Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Amar J Majmundar
- Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA
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Okabe M, Okabayashi Y, Sasaki T, Koike K, Tsuboi N, Matsusaka T, Yokoo T. Podocyte Injury and Long-Term Kidney Prognosis in Patients with Lupus Nephritis. KIDNEY360 2025; 6:606-615. [PMID: 39714942 PMCID: PMC12045515 DOI: 10.34067/kid.0000000688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 12/18/2024] [Indexed: 12/25/2024]
Abstract
Key Points Podocyte injury, as indicated by early growth response 1 expression, was correlated with the clinical and histopathological activities of lupus nephritis (LN). Podocyte injury was associated with poor long-term kidney prognosis in patients with active LN. To improve the prognosis of patients with LN, treatment strategies on the basis of the degree of podocyte injury may be considered. Background Lupus nephritis (LN) is a major complication of SLE. Like other types of GN, podocyte injury has been observed in patients with LN. However, the association between podocyte injury and kidney prognosis in patients with LN has not been well elucidated. The aim of this study was to explore the association between podocyte injury and clinical and histological status and kidney prognosis in patients with LN. Methods Seventy-five patients histopathologically diagnosed with LN were enrolled in this study. Early growth response 1 (EGR1) expression in podocytes, representing podocyte injury, was detected through immunohistochemistry. The correlation between the proportion of glomeruli with podocytes expressing EGR1 (%EGR1glo) and the clinical and histological features of LN were evaluated. Subsequently, the association between %EGR1glo and kidney prognosis was examined in a group of patients with LN class 3, 4, or 5 who showed ≥0.5 g/g of urinary protein–creatinine ratio and received immunosuppressive therapy. Hazard ratio was calculated using univariate Cox proportional hazards regression. Results %EGR1glo was highest in patients with LN class 4, significantly correlated with the SLE Disease Activity Index score, urinary protein level, and prevalence of glomeruli showing cellular/fibrocellular crescents, endocapillary hypercellularity, and fibrinoid necrosis and inversely correlated with eGFR. Higher %EGR1glo was significantly associated with sustained ≥30% eGFR decline over 10 years in patients with LN class 3, 4, or 5 (n =42; hazard ratio, 1.58 [95% confidence interval, 1.07 to 2.36] per 10% increase in %EGR1glo). There was no significant interaction between patients grouped by kidney function, urinary protein level, presence of cellular/fibrocellular crescents, degree of tubulointerstitial fibrosis, and LN classification. Conclusions Podocyte damage, as indicated by EGR1 expression, was associated with poor long-term kidney prognosis in patients with active LN. Treatment strategies on the basis of the extent of podocyte injury may be necessary.
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Affiliation(s)
- Masahiro Okabe
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Yusuke Okabayashi
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Takaya Sasaki
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Kentaro Koike
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Nobuo Tsuboi
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Taiji Matsusaka
- Department of Basic Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Takashi Yokoo
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
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Wang L, Tang Y, Buckley AF, Spurney RF. Podocyte specific knockout of the natriuretic peptide clearance receptor is podocyte protective in focal segmental glomerulosclerosis. PLoS One 2025; 20:e0319424. [PMID: 40063586 PMCID: PMC11892885 DOI: 10.1371/journal.pone.0319424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 01/31/2025] [Indexed: 05/13/2025] Open
Abstract
Natriuretic peptides (NPs) bind to glomerular podocytes and attenuate glomerular injury. The beneficial effects of NPs are negatively regulated by the NP clearance receptor (NPRC), which is highly expressed in podocytes. To determine if inhibiting NPRC is podocyte protective, we examined the effects of deleting NPRC in both cultured podocytes and in vivo. We found that: 1.Both atrial NP and C-type NP inhibit podocyte apoptosis in cultured podocytes, but these podocyte protective effects are significantly attenuated in cells expressing NPRC, and 2. Atrial NP was significantly more effective than CNP at inhibiting the apoptotic response. Consistent with the protective actions of NPs, podocyte specific knockout of NPRC reduced albuminuria, glomerular sclerosis and tubulointerstitial inflammation in a mouse model of focal segmental glomerulosclerosis. These beneficial actions were associated with: 1. Decreased expression of the myofibroblast marker alpha-smooth muscle actin, 2. Reduced expression of the extracellular matrix proteins collagen 4-alpha-1 and fibronectin, and 3. Preserved expression of the podocyte proteins nephrin and podocin. Inhibiting NP clearance may be a useful therapeutic approach to treat glomerular diseases.
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MESH Headings
- Podocytes/metabolism
- Podocytes/pathology
- Podocytes/drug effects
- Animals
- Glomerulosclerosis, Focal Segmental/pathology
- Glomerulosclerosis, Focal Segmental/metabolism
- Glomerulosclerosis, Focal Segmental/genetics
- Receptors, Atrial Natriuretic Factor/genetics
- Receptors, Atrial Natriuretic Factor/metabolism
- Receptors, Atrial Natriuretic Factor/deficiency
- Mice
- Apoptosis/drug effects
- Mice, Knockout
- Natriuretic Peptide, C-Type/pharmacology
- Natriuretic Peptide, C-Type/metabolism
- Disease Models, Animal
- Membrane Proteins/metabolism
- Albuminuria/genetics
- Male
- Intracellular Signaling Peptides and Proteins
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Affiliation(s)
- Liming Wang
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina, United States of America
| | - Yuping Tang
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina, United States of America
| | - Anne F. Buckley
- Department of Pathology, Duke University Medical Center, Durham, North Carolina, United States of America
| | - Robert F. Spurney
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina, United States of America
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Yao L, Li Y, Wang P, Xu C, Yu Z. Nucleoporin-associated steroid-resistant nephrotic syndrome. Pediatr Nephrol 2025; 40:629-649. [PMID: 39331077 DOI: 10.1007/s00467-024-06494-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 08/01/2024] [Accepted: 08/07/2024] [Indexed: 09/28/2024]
Abstract
Nucleoporins (Nups) are a class of proteins that assemble to form nuclear pore complexes, which are related to nucleocytoplasmic transport, gene expression, and the cell cycle. Pathogenic variants in six genes encoding Nups, NUP85, NUP93, NUP107, NUP133, NUP160, and NUP205, cause monogenic steroid-resistant nephrotic syndrome (SRNS), referred to as nucleoporin-associated SRNS. In this paper, we review the epidemiology, structure and function of Nups, pathogenesis, phenotypes and genotypes, and management of nucleoporin-associated SRNS as well as implications for genetic counseling. Affected individuals exhibit autosomal recessive isolated and syndromic SRNS, whose extrarenal manifestations include neurological disorders, growth and development disorders, cardiovascular disorders, and congenital malformations. The median ages at onset of NUP85-, NUP93-, NUP107-, NUP133-, NUP160-, and NUP205-associated SRNS are 7, 3, 4.1, 9, 7, and 2 years, respectively. Kidney biopsies reveal focal segmental glomerulosclerosis in 89% of patients. Most affected individuals are resistant to immunosuppressants. For the six subtypes of nucleoporin-associated SRNS, patients show progression to kidney failure at median ages of 8.5, 3.7, 6.9, 13, 15, and 7 years, respectively. Only two patients with NUP93-associated SRNS with nephrotic syndrome relapse post-transplant have been reported, and the recurrence rate is 12.5%. Next-generation sequencing using a targeted gene panel is recommended in cases of suspected nucleoporin-associated SRNS for genetic diagnosis. Renin-angiotensin-aldosterone system inhibitors are recommended for patients with nucleoporin-associated SRNS. Once genetic diagnosis is confirmed, immunosuppressant discontinuation should be considered, and kidney transplant is preferred when patients progress to kidney failure. Genetic counselling should be provided for asymptomatic siblings and future siblings of an affected individual. Further studies on the pathogenesis of nucleoporin-associated SRNS are needed to seek new therapeutic interventions.
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Affiliation(s)
- Ling Yao
- Department of Nephrology, Rheumatology and Immunology, Fujian Children's Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, 966 Heng Yu Road, Jin'an District, Fuzhou, 350014, Fujian, People's Republic of China
| | - Yuanyuan Li
- Department of Nephrology, Rheumatology and Immunology, Fujian Children's Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, 966 Heng Yu Road, Jin'an District, Fuzhou, 350014, Fujian, People's Republic of China
| | - Ping Wang
- Department of Pediatrics, The Military Hospital of 92435 Unit of PLA, Ningde, 352103, China
| | - Chan Xu
- Department of Nephrology, Rheumatology and Immunology, Fujian Children's Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, 966 Heng Yu Road, Jin'an District, Fuzhou, 350014, Fujian, People's Republic of China
| | - Zihua Yu
- Department of Nephrology, Rheumatology and Immunology, Fujian Children's Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, 966 Heng Yu Road, Jin'an District, Fuzhou, 350014, Fujian, People's Republic of China.
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Fan X, Li J, Gao Y, Li L, Zhang H, Bi Z. The mechanism of enterogenous toxin methylmalonic acid aggravating calcium-phosphorus metabolic disorder in uremic rats by regulating the Wnt/β-catenin pathway. Mol Med 2025; 31:19. [PMID: 39844078 PMCID: PMC11756144 DOI: 10.1186/s10020-025-01067-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 01/03/2025] [Indexed: 01/24/2025] Open
Abstract
BACKGROUND Uremia (UR) is caused by increased UR-related toxins in the bloodstream. We explored the mechanism of enterogenous toxin methylmalonic acid (MMA) in calcium-phosphorus metabolic disorder in UR rats via the Wnt/β-catenin pathway. METHODS The UR rat model was established by 5/6 nephrectomy. The fecal bacteria of UR rats were transplanted into Sham rats. Sham rats were injected with exogenous MMA or Salinomycin (SAL). Pathological changes in renal/colon tissues were analyzed. MMA concentration, levels of renal function indicators, serum inflammatory factors, Ca2+/P3+, and parathyroid hormone, intestinal flora structure, fecal metabolic profile, intestinal permeability, and glomerular filtration rate (GFR) were assessed. Additionally, rat glomerular podocytes were cultured, with cell viability and apoptosis measured. RESULTS Intestinal flora richness and diversity in UR rats were decreased, along with unbalanced flora structure. Among the screened 133 secondary differential metabolites, the MMA concentration rose, showing the most significant difference. UR rat fecal transplantation caused elevated MMA concentration in the serum and renal tissues of Sham rats. The intestinal flora metabolite MMA or exogenous MMA promoted intestinal barrier impairment, increased intestinal permeability, induced glomerular podocyte loss, and reduced GFR, causing calcium-phosphorus metabolic disorder. The intestinal flora metabolite MMA or exogenous MMA induced inflammatory responses and facilitated glomerular podocyte apoptosis by activating the Wnt/β-catenin pathway, which could be counteracted by repressing the Wnt/β-catenin pathway. CONCLUSIONS Enterogenous toxin MMA impelled intestinal barrier impairment in UR rats, enhanced intestinal permeability, and activated the Wnt/β-catenin pathway to induce glomerular podocyte loss and reduce GFR, thus aggravating calcium-phosphorus metabolic disorder.
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Affiliation(s)
- Xing Fan
- Department of Nephrology, The Affiliated Hospital of Hebei University, No. 212 Yuhua East Road, Lianchi District, Baoding, 071000, Hebei Province, China
- Key Laboratory of Bone Metabolism and Physiology in Chronic Kidney Disease of Hebei Province, No. 212 Yuhua East Road, Lianchi District, Baoding, 071000, Hebei Province, China
| | - Jing Li
- Department of Nephrology, The Affiliated Hospital of Hebei University, No. 212 Yuhua East Road, Lianchi District, Baoding, 071000, Hebei Province, China
- Key Laboratory of Bone Metabolism and Physiology in Chronic Kidney Disease of Hebei Province, No. 212 Yuhua East Road, Lianchi District, Baoding, 071000, Hebei Province, China
| | - Yan Gao
- Department of Nephrology, The Affiliated Hospital of Hebei University, No. 212 Yuhua East Road, Lianchi District, Baoding, 071000, Hebei Province, China.
- Key Laboratory of Bone Metabolism and Physiology in Chronic Kidney Disease of Hebei Province, No. 212 Yuhua East Road, Lianchi District, Baoding, 071000, Hebei Province, China.
| | - Lin Li
- Department of Nephrology, The Affiliated Hospital of Hebei University, No. 212 Yuhua East Road, Lianchi District, Baoding, 071000, Hebei Province, China.
- Key Laboratory of Bone Metabolism and Physiology in Chronic Kidney Disease of Hebei Province, No. 212 Yuhua East Road, Lianchi District, Baoding, 071000, Hebei Province, China.
| | - Haisong Zhang
- Department of Nephrology, The Affiliated Hospital of Hebei University, No. 212 Yuhua East Road, Lianchi District, Baoding, 071000, Hebei Province, China
- Key Laboratory of Bone Metabolism and Physiology in Chronic Kidney Disease of Hebei Province, No. 212 Yuhua East Road, Lianchi District, Baoding, 071000, Hebei Province, China
| | - Zhaoyu Bi
- Department of Nephrology, The Affiliated Hospital of Hebei University, No. 212 Yuhua East Road, Lianchi District, Baoding, 071000, Hebei Province, China
- Key Laboratory of Bone Metabolism and Physiology in Chronic Kidney Disease of Hebei Province, No. 212 Yuhua East Road, Lianchi District, Baoding, 071000, Hebei Province, China
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Liu F, Xu Z, Chen G, Xu X, Cao H, Chen J. Evolutionary patterns and research frontiers in autophagy in podocytopathies: a bibliometric analysis. Front Med (Lausanne) 2025; 11:1445550. [PMID: 39850100 PMCID: PMC11754056 DOI: 10.3389/fmed.2024.1445550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 12/23/2024] [Indexed: 01/25/2025] Open
Abstract
Introduction Podocytopathies are a uniquely renal disease syndrome, in which direct or indirect podocyte injury leads to proteinuria or nephrotic syndrome. Of the many factors that contribute to podocytopathies, the abnormal regulation of autophagy, such insufficient or excessive autophagy levels, have been proposed to play a significant role in the occurrence and development of podocytopathies. However, there still has been a lack of systematic and comparative research to elucidate exact role of autophagy in podocytopathies and its current research status. This study aims to utilize bibliometric analysis to clarify the role of autophagy in the pathogenesis of podocytopathies, analyze the research focus in this area, as well as explore the future research trends. Methods We retrieved original articles and review papers with respect to autophagy in podocytopathies research published between the year 2008 and 2022 from the Web of Science Core Collection (WOSCC). Then, VOSviewer and CiteSpace software were employed to reveal the leading subjects and generate visual maps of countries/regions, organizations, authors, journals, and keyword networks in this field. Results and discussion A total of 825 publications regarding autophagy in podocytopathies published between 2008 and 2022 were included, with China contributing the most followed by the United States and Japan. Professor Koya Daisuke, Professor He Qiang, and Professor Jin Juan are the most prolific researchers in this field. Oxidative stress, the NLRP3 inflammasome, and therapeutic targets were the knowledge base for the research in this special field. Taken together, this bibliometric analysis helps us reveal the current research hotspots and guide future research directions, which provides a reference for scholars to further investigate the role of autophagy in podocytopathies as well as conduct clinical trial with autophagy regulators in podocytopathies.
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Affiliation(s)
- Feng Liu
- Department of Nephrology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Ziyu Xu
- Department of Nephrology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Gaijie Chen
- Health Management Center, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaojing Xu
- Department of Respiratory and Critical Care Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Huixia Cao
- Department of Nephrology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Jiefang Chen
- Department of Neurology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
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Zhang Y, Wang F, Zhang C, Yao F, Zhang B, Zhang Y, Sun X. FGF21 ameliorates diabetic nephropathy through CDK1-dependently regulating the cell cycle. Front Pharmacol 2025; 15:1500458. [PMID: 39830349 PMCID: PMC11739279 DOI: 10.3389/fphar.2024.1500458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 12/06/2024] [Indexed: 01/22/2025] Open
Abstract
Background Diabetic nephropathy (DN) is a prevalent global renal illness and one of the main causes of end-stage renal disease (ESRD). FGF21 has been shown to ameliorate diabetic nephropathy, and in addition FGF-21-treated mice impeded mitogenicity, whereas it is unclear whether FGF21 can influence DN progression by regulating the cell cycle in diabetic nephropathy. Methods In order to create a diabetic model, STZ injections were given to C57BL/6J mice for this investigation. Then, FGF21 was administered, and renal tissue examination and pathological observation were combined with an assessment of glomerular injury, inflammation, oxidative stress, and the fibrinogen system in mice following the administration of the intervention. Furthermore, we used db/db mice and FGF21 direct therapy for 8 weeks to investigate changes in fasting glucose and creatinine expression as well as pathological changes in glomeruli glycogen deposition, fibrosis, and nephrin expression. To investigate the mechanism of action of FGF21 in the treatment of glycolytic kidney, transcriptome sequencing of renal tissues and KEGG pathway enrichment analysis of differential genes were performed. Results The study's findings demonstrated that FGF21 intervention increased clotting time, decreased oxidative stress and inflammation, and avoided thrombosis in addition to considerably improving glomerular filtration damage. After 8 weeks of FGF21 treatment, glomerular glycogen deposition, fibrosis, and renin expression decreased in db/db mice. Moreover, there was a notable reduction of creatinine and fasting blood glucose levels. Additionally, the CDK1 gene, a key player in controlling the cell cycle, was discovered through examination of the transcriptome sequencing data. It was also shown that FGF21 dramatically reduces the expression of CDK1, which may help diabetic nephropathy by averting mitotic catastrophe and changing the renal cell cycle. Conclusion In short, FGF21 improved the development of diabetic nephropathy in diabetic nephropathy-affected animals by reducing glomerular filtration damage, inflammation, and oxidative stress, inhibiting the formation of thrombus, and controlling the cell cycle through CDK1.
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Affiliation(s)
- Yudie Zhang
- Guizhou University of Traditional Chinese Medicine, Guiyang, China
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of efficacy evaluation of Chinese Medicine Against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing, China
| | - Fan Wang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of efficacy evaluation of Chinese Medicine Against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing, China
| | - Chongyang Zhang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of efficacy evaluation of Chinese Medicine Against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing, China
| | - Fan Yao
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of efficacy evaluation of Chinese Medicine Against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing, China
| | - Bin Zhang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of efficacy evaluation of Chinese Medicine Against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing, China
| | - Yongping Zhang
- Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Xiaobo Sun
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of efficacy evaluation of Chinese Medicine Against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing, China
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Schneider R, Mansour B, Kolvenbach CM, Buerger F, Salmanullah D, Lemberg K, Merz LM, Mertens ND, Saida K, Yousef K, Franken GAC, Bao A, Yu S, Hölzel S, Nicolas-Frank C, Steinsapir A, Goncalves KA, Shril S, Hildebrandt F. Phenotypic quantification of Nphs1-deficient mice. J Nephrol 2025; 38:143-152. [PMID: 39003671 PMCID: PMC11772050 DOI: 10.1007/s40620-024-01987-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 05/06/2024] [Indexed: 07/15/2024]
Abstract
BACKGROUND Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of chronic kidney disease in children and young adults. The most severe form of steroid-resistant nephrotic syndrome is congenital nephrotic syndrome Finnish type (CNSF), caused by biallelic loss-of-function variants in NPHS1, encoding nephrin. Since each of the 68 monogenic causes of steroid-resistant nephrotic syndrome represents a rare cause of the disease, tailoring therapeutic interventions to multiple molecular targets remains challenging, suggesting gene replacement therapy (GRT) as a viable alternative. To set the ground for a gene replacement study in vivo, we established rigorous, quantifiable, and reproducible phenotypic assessment of a conditional Nphs1 knockout mouse model. METHODS By breeding a floxed Nphs1fl/- mouse (Nphs1tm1Afrn/J) previously studied for pancreatic β-cell survival with a podocin promoter-driven Cre recombinase mouse model (Tg(NPHS2-Cre)295Lbh/J), we generated mice with podocyte-specific nephrin deficiency (Nphs1fl/fl NPHS2-Cre +). RESULTS We observed a median survival to postnatal day P5 in nephrin-deficient mice, whereas heterozygous control mice and wild type (WT) control group showed 90% and 100% survival, respectively (at P50 days). Light microscopy analysis showed a significantly higher number of renal-tubular microcysts per kidney section in nephrin-deficient mice compared to the control groups (P < 0.0022). Transmission electron microscopy demonstrated reduced foot process (FP) density in nephrin-deficient mice compared to controls (P < 0.0001). Additionally, proteinuria quantitation using urine albumin-to-creatinine ratio (UACR) was significantly higher in nephrin-deficient mice compared to controls. CONCLUSIONS This study represents the first comprehensive description of the kidney phenotype in a nephrin-deficient mouse model, laying the foundation for future gene replacement therapy endeavors.
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Affiliation(s)
- Ronen Schneider
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA
| | - Bshara Mansour
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA
| | - Caroline M Kolvenbach
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA
- Institute of Anatomy and Cell Biology, Medical Faculty, University of Bonn, Bonn, Germany
| | - Florian Buerger
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA
| | - Daanya Salmanullah
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA
| | - Katharina Lemberg
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA
| | - Lea M Merz
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA
- Department of Pediatrics, University Leipzig, Leipzig, Germany
| | - Nils D Mertens
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA
| | - Ken Saida
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA
| | - Kirollos Yousef
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA
| | - Gijs A C Franken
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA
| | - Aaron Bao
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA
| | - Seyoung Yu
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA
| | - Selina Hölzel
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA
| | - Camille Nicolas-Frank
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA
| | - Andrew Steinsapir
- Deerfield Discovery and Development, Deerfield Management Company, L.P. (Series C), New York, USA
| | - Kevin A Goncalves
- Deerfield Discovery and Development, Deerfield Management Company, L.P. (Series C), New York, USA
| | - Shirlee Shril
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA
| | - Friedhelm Hildebrandt
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA.
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10
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Altintas MM, Agarwal S, Sudhini Y, Zhu K, Wei C, Reiser J. Pathogenesis of Focal Segmental Glomerulosclerosis and Related Disorders. ANNUAL REVIEW OF PATHOLOGY 2025; 20:329-353. [PMID: 39854184 PMCID: PMC11875227 DOI: 10.1146/annurev-pathol-051220-092001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2025]
Abstract
Focal segmental glomerulosclerosis (FSGS) is the morphologic manifestation of a spectrum of kidney diseases that primarily impact podocytes, cells that create the filtration barrier of the glomerulus. As its name implies, only parts of the kidney and glomeruli are affected, and only a portion of the affected glomerulus may be sclerosed. Although the diagnosis is based primarily on microscopic features, patient stratification relies on clinical data such as proteinuria and etiological criteria. FSGS affects both children and adults and has an elevated risk of progression to end-stage renal disease. The prevalence of FSGS is rising among various populations, and the efficacy of various therapies is limited. Therefore, understanding the pathophysiology of FSGS and developing targeted therapies to address the complex needs of FSGS patients are topics of great interest that are currently being studied across various clinical trials. We discuss the etiology of FSGS, describe the major contributing pathophysiological pathways, and outline emerging therapeutic strategies along with their pitfalls.
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Affiliation(s)
- Mehmet M Altintas
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA;
| | | | - Yashwanth Sudhini
- Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Ke Zhu
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA;
| | - Changli Wei
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA;
| | - Jochen Reiser
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA;
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11
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Li K, Liu X, Zhang L, Ding F. Increased urinary podocyte mRNA loss in healthy early-term infants. Pediatr Nephrol 2024:10.1007/s00467-024-06639-4. [PMID: 39708124 DOI: 10.1007/s00467-024-06639-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 12/04/2024] [Accepted: 12/05/2024] [Indexed: 12/23/2024]
Affiliation(s)
- Kong Li
- Department of Neonatology, Tianjin Central Hospital of Obstetrics and Gynecology, No. 156 Nan Kai San Ma Lu, Tianjin, P.R. China, 300000
- Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin, China
- Department of Neonatology, Nankai University Maternity Hospital, Tianjin, China
| | - Xueou Liu
- Research Institute of Obstetrics and Gynecology, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China
| | - Lulu Zhang
- Department of Neonatology, Tianjin Central Hospital of Obstetrics and Gynecology, No. 156 Nan Kai San Ma Lu, Tianjin, P.R. China, 300000
- Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin, China
- Department of Neonatology, Nankai University Maternity Hospital, Tianjin, China
| | - Fangrui Ding
- Department of Neonatology, Tianjin Central Hospital of Obstetrics and Gynecology, No. 156 Nan Kai San Ma Lu, Tianjin, P.R. China, 300000.
- Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin, China.
- Department of Neonatology, Nankai University Maternity Hospital, Tianjin, China.
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12
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Yu T, Ji Y, Cui X, Liang N, Wu S, Xiang C, Li Y, Tao H, Xie Y, Zuo H, Wang W, Khan N, Ullah K, Xu F, Zhang Y, Lin C. Novel Pathogenic Mutation of P209L in TRPC6 Gene Causes Adult Focal Segmental Glomerulosclerosis. Biochem Genet 2024; 62:4432-4445. [PMID: 38315264 DOI: 10.1007/s10528-023-10651-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 12/27/2023] [Indexed: 02/07/2024]
Abstract
Focal segmental glomerulosclerosis (FSGS) is a leading kidney disease, clinically associated with proteinuria and progressive renal failure. The occurrence of this disease is partly related to gene mutations. We describe a single affected family member who presented with FSGS. We used high-throughput sequencing, sanger sequencing to identify the pathogenic mutations, and a systems genetics analysis in the BXD mice was conducted to explore the genetic regulatory mechanisms of pathogenic genes in the development of FSGS. We identified high urinary protein (++++) and creatinine levels (149 μmol/L) in a 29-year-old male diagnosed with a 5-year history of grade 2 hypertension. Histopathology of the kidney biopsy showed stromal hyperplasia at the glomerular segmental sclerosis and endothelial cell vacuolation degeneration. Whole-exome sequencing followed by Sanger sequencing revealed a heterozygous missense mutation (c.643C > T) in exon 2 of TRPC6, leading to the substitution of arginine with tryptophan at position 215 (p.Arg215Trp). Systems genetics analysis of the 53 BXD mice kidney transcriptomes identified Pygm as the upstream regulator of Trpc6. Those two genes are jointly involved in the regulation of FSGS mainly via Wnt and Hippo signaling pathways. We present a novel variant in the TRPC6 gene that causes FSGS. Moreover, our data suggested TRPC6 works with PYGM, as well as Wnt and Hippo signaling pathways to regulate renal function, which could guide future clinical prevention and targeted treatment for FSGS outcomes.
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Affiliation(s)
- Tianxi Yu
- School of Clinical Medicine, Weifang Medical University, Weifang, 261042, China
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, Shandong, China
| | - Yongqiang Ji
- Department of Nephrology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, Shandong, China
| | - Xin Cui
- School of Clinical Medicine, Weifang Medical University, Weifang, 261042, China
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, Shandong, China
| | - Ning Liang
- School of Clinical Medicine, Weifang Medical University, Weifang, 261042, China
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, Shandong, China
| | - Shuang Wu
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, Shandong, China
| | - Chongjun Xiang
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, Shandong, China
- The 2nd Medical College of Binzhou Medical University, Yantai, 264003, Shandong, China
| | - Yue Li
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, Shandong, China
- The 2nd Medical College of Binzhou Medical University, Yantai, 264003, Shandong, China
| | - Huiying Tao
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, Shandong, China
- The 2nd Medical College of Binzhou Medical University, Yantai, 264003, Shandong, China
| | - Yaqi Xie
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, Shandong, China
- The 2nd Medical College of Binzhou Medical University, Yantai, 264003, Shandong, China
| | - Hongwei Zuo
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, Shandong, China
- The 2nd Medical College of Binzhou Medical University, Yantai, 264003, Shandong, China
| | - Wenting Wang
- Central Laboratory, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, Shandong, China
| | - Nauman Khan
- Department of Biology, Faculty of Biological and Biomedical Sciences, The University of Haripur, Haripur, KP, Pakistan
| | - Kamran Ullah
- Department of Biology, Faculty of Biological and Biomedical Sciences, The University of Haripur, Haripur, KP, Pakistan
| | - Fuyi Xu
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, 264003, Shandong, China
| | - Yan Zhang
- Department of Nephrology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, Shandong, China.
| | - Chunhua Lin
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, Shandong, China.
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13
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Liu PJ, Sayeeda K, Zhuang C, Krendel M. Roles of myosin 1e and the actin cytoskeleton in kidney functions and familial kidney disease. Cytoskeleton (Hoboken) 2024; 81:737-752. [PMID: 38708443 PMCID: PMC11538376 DOI: 10.1002/cm.21861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 03/21/2024] [Accepted: 04/04/2024] [Indexed: 05/07/2024]
Abstract
Mammalian kidneys are responsible for removing metabolic waste and maintaining fluid and electrolyte homeostasis via selective filtration. One of the proteins closely linked to selective renal filtration is myosin 1e (Myo1e), an actin-dependent molecular motor found in the specialized kidney epithelial cells involved in the assembly and maintenance of the renal filter. Point mutations in the gene encoding Myo1e, MYO1E, have been linked to familial kidney disease, and Myo1e knockout in mice leads to the disruption of selective filtration. In this review, we discuss the role of the actin cytoskeleton in renal filtration, the known and hypothesized functions of Myo1e, and the possible explanations for the impact of MYO1E mutations on renal function.
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Affiliation(s)
- Pei-Ju Liu
- Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, NY 13210
| | - Kazi Sayeeda
- Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, NY 13210
| | - Cindy Zhuang
- Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, NY 13210
| | - Mira Krendel
- Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, NY 13210
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14
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Maggiore JC, LeGraw R, Przepiorski A, Velazquez J, Chaney C, Vanichapol T, Streeter E, Almuallim Z, Oda A, Chiba T, Silva-Barbosa A, Franks J, Hislop J, Hill A, Wu H, Pfister K, Howden SE, Watkins SC, Little MH, Humphreys BD, Kiani S, Watson A, Stolz DB, Davidson AJ, Carroll T, Cleaver O, Sims-Lucas S, Ebrahimkhani MR, Hukriede NA. A genetically inducible endothelial niche enables vascularization of human kidney organoids with multilineage maturation and emergence of renin expressing cells. Kidney Int 2024; 106:1086-1100. [PMID: 38901605 PMCID: PMC11912416 DOI: 10.1016/j.kint.2024.05.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 05/10/2024] [Accepted: 05/24/2024] [Indexed: 06/22/2024]
Abstract
Vascularization plays a critical role in organ maturation and cell-type development. Drug discovery, organ mimicry, and ultimately transplantation hinge on achieving robust vascularization of in vitro engineered organs. Here, focusing on human kidney organoids, we overcame this hurdle by combining a human induced pluripotent stem cell (iPSC) line containing an inducible ETS translocation variant 2 (ETV2) (a transcription factor playing a role in endothelial cell development) that directs endothelial differentiation in vitro, with a non-transgenic iPSC line in suspension organoid culture. The resulting human kidney organoids show extensive endothelialization with a cellular identity most closely related to human kidney endothelia. Endothelialized kidney organoids also show increased maturation of nephron structures, an associated fenestrated endothelium with de novo formation of glomerular and venous subtypes, and the emergence of drug-responsive renin expressing cells. The creation of an engineered vascular niche capable of improving kidney organoid maturation and cell type complexity is a significant step forward in the path to clinical translation. Thus, incorporation of an engineered endothelial niche into a previously published kidney organoid protocol allowed the orthogonal differentiation of endothelial and parenchymal cell types, demonstrating the potential for applicability to other basic and translational organoid studies.
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Affiliation(s)
- Joseph C Maggiore
- Department of Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Center for Integrative Organ Systems, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Ryan LeGraw
- Department of Pathology, Division of Experimental Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Aneta Przepiorski
- Department of Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Jeremy Velazquez
- Department of Pathology, Division of Experimental Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Christopher Chaney
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Thitinee Vanichapol
- Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
| | - Evan Streeter
- Department of Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Center for Integrative Organ Systems, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Zainab Almuallim
- Department of Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Center for Integrative Organ Systems, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Akira Oda
- Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh Pennsylvania, USA
| | - Takuto Chiba
- Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh Pennsylvania, USA
| | - Anne Silva-Barbosa
- Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh Pennsylvania, USA
| | - Jonathan Franks
- Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Joshua Hislop
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Alex Hill
- Department of Pathology, Division of Experimental Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Haojia Wu
- Division of Nephrology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Katherine Pfister
- Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh Pennsylvania, USA
| | - Sara E Howden
- Murdoch Children's Research Institute, Melbourne, Victoria, Australia
| | - Simon C Watkins
- Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Melissa H Little
- Murdoch Children's Research Institute, Melbourne, Victoria, Australia; Department of Anatomy and Neuroscience, The University of Melbourne, Melbourne, Victoria, Australia; Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia
| | - Benjamin D Humphreys
- Division of Nephrology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA; Department of Developmental Biology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Samira Kiani
- Department of Pathology, Division of Experimental Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Alan Watson
- Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Donna B Stolz
- Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Alan J Davidson
- Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
| | - Tom Carroll
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Ondine Cleaver
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Sunder Sims-Lucas
- Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh Pennsylvania, USA
| | - Mo R Ebrahimkhani
- Department of Pathology, Division of Experimental Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
| | - Neil A Hukriede
- Department of Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Center for Integrative Organ Systems, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
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15
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Ibrahim A, Altawallbeh Z, Revelo MP, Gregory M, Al-Rabadi L. Ocular Coherence Tomography Unveils Alport Syndrome: A Critical Tool in Detecting Collagen IV Nephropathies. Case Rep Nephrol 2024; 2024:5087883. [PMID: 39588246 PMCID: PMC11588406 DOI: 10.1155/crin/5087883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 10/29/2024] [Indexed: 11/27/2024] Open
Abstract
Collagen IV pathogenic variants are present in Alport syndrome (AS) and some forms of familial focal segmental glomerulosclerosis (FSGS). These conditions pose diagnostic challenges due to overlapping clinical, histological, and genetic features. Ocular coherence tomography (OCT) has emerged as a pivotal diagnostic tool by revealing ocular manifestations characteristic of AS. Here, we present two cases initially diagnosed with primary FSGS but later found to harbor collagen IV pathogenic variants. Both cases progressed to end-stage kidney disease (ESKD) needing transplantation. OCT revealed severe temporal macular thinning consistent with AS in both cases. Our findings highlight the critical role of OCT in distinguishing the subtle differences in the presentation of collagen IV nephropathies. OCT proves valuable for clinicians, particularly when COL4 nephropathies present ambiguous or overlapping features. In such instances, OCT serves to establish precise diagnoses, preventing unnecessary immune suppression. Therefore, incorporating OCT alongside genetic and histological evaluations is crucial for accurate diagnosis, management, and appropriate genetic counseling. Furthermore, recognizing the prevalence of AS accurately is pivotal for conducting population-based studies, which are essential for advancing our understanding of the condition, improving patient care, and informing future research initiatives.
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Affiliation(s)
| | - Zena Altawallbeh
- Nephrology Department, University of Utah Health, Salt Lake City, Utah, USA
| | | | - Martin Gregory
- Nephrology Department, University of Utah Health, Salt Lake City, Utah, USA
| | - Laith Al-Rabadi
- Nephrology Department, University of Utah Health, Salt Lake City, Utah, USA
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16
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Boruah D, Kashif AW, Chakrabarty BK, Harikrishnan S, Sen A. Correlation of light and electron microscopic morphometric parameters of glomerular capillaries with serum creatinine and proteinuria. J Histotechnol 2024; 47:97-108. [PMID: 38465441 DOI: 10.1080/01478885.2024.2326274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 02/27/2024] [Indexed: 03/12/2024]
Abstract
Waste products in the bloodstream are filtered by the glomerular capillaries in the kidneys and excreted into the urine. When making a differential diagnosis of kidney diseases, structural assessment of glomeruli using histological, ultrastructural, and immunological studies is crucial. This study assessed the microscopic and ultrastructural morphometric parameters of glomerular capillaries and examined their correlation with serum creatinine and proteinuria. A total of 60 kidney biopsy cases received by the transmission electron microscope (TEM) laboratory for diagnosis were included in the study. Toluidine blue stained 300 nm thick sections of TEM tissue blocks were scanned for glomerular morphometry by a whole slide imaging system, and the estimation of Bowman's capsule (BC) area, glomerular capillary lumen diameter (GCLD), glomerular capillary density (GCD), glomerular capillary surface area density (GCSA), and percentage of glomerular capillary lumen space (%GCLS) was performed with QuPath software. TEM images of 70 nm thick sections were used for the evaluation of endothelial fenestration diameter (EFD), glomerular basement membrane (GBM) thickness, and podocyte foot process (PFP) effacement. Proteinuria and serum creatinine showed positive correlations with GBM thickness and PFP effacement. Negative correlations of serum creatinine were observed with EFD, %GCLS, and GCSA. Hence, glomerular filtration is greatly affected by the total area of the glomerular capillary surface and structural changes of GBM. Reduction of glomerulus filtration due to foot process effacement and thickening of GBM results in damage to the filtration barrier leading to the leakage of plasma protein into urine.
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Affiliation(s)
| | - A W Kashif
- Department of Pathology, Armed Forces Medical College, Pune, India
| | | | | | - Arijit Sen
- Department of Pathology, Armed Forces Medical College, Pune, India
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17
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Hu X, Lin W, Luo Z, Zhong Y, Xiao X, Tang R. Frameshift Mutation in PAX2 Related to Focal Segmental Glomerular Sclerosis: A Case Report and Literature Review. Mol Genet Genomic Med 2024; 12:e70006. [PMID: 39235128 PMCID: PMC11375732 DOI: 10.1002/mgg3.70006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 08/14/2024] [Accepted: 08/20/2024] [Indexed: 09/06/2024] Open
Abstract
BACKGROUND Paired box gene 2 (PAX2) heterozygous mutations can cause renal coloboma syndrome, but its role in patients with focal segmental glomerular sclerosis (FSGS) has been rarely reported. METHODS Based on the clinical manifestations and renal pathological characteristics of the patient, as well as familial whole exome sequencing, the diagnosis of FSGS related to PAX2 mutation was confirmed. Treatment such as lowering urinary protein and blood pressure was given, and the patient was followed up and observed. RESULTS There is a familial heterozygous case presented with chronic kidney disease secondary to FSGS, which was related to PAX2 frameshift mutation due to the deletion of G at the position 76 (c.76delG). To our knowledge, this is the first report of PAX2 c.76delG variant related to adult-onset FSGS. CONCLUSION Here, we further expand the phenotypic spectrum of FSGS. Genetic screening especially PAX2 mutation is recommended in patients with adult-onset FSGS of unknown etiology.
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Affiliation(s)
- Xueling Hu
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
| | - Wei Lin
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Zengyuan Luo
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
| | - Yong Zhong
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
| | - Xiangcheng Xiao
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
| | - Rong Tang
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
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18
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Haruhara K, Okabayashi Y, Sasaki T, Kubo E, D'Agati VD, Bertram JF, Tsuboi N, Yokoo T. Podocyte density as a predictor of long-term kidney outcome in obesity-related glomerulopathy. Kidney Int 2024; 106:496-507. [PMID: 39046396 DOI: 10.1016/j.kint.2024.05.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 05/15/2024] [Accepted: 05/28/2024] [Indexed: 07/25/2024]
Abstract
Glomerulomegaly and focal segmental glomerulosclerosis are histopathological hallmarks of obesity-related glomerulopathy (ORG). Podocyte injury and subsequent depletion are regarded as key processes in the development of these glomerular lesions in patients with ORG, but their impact on long-term kidney outcome is undetermined. Here, we correlated clinicopathological findings and podocyte depletion retrospectively in patients with ORG. Relative (podocyte density) and absolute (podocyte number per glomerulus) measures of podocyte depletion were estimated using model-based stereology in 46 patients with ORG. The combined endpoint of kidney outcomes was defined as a 30% decline in estimated glomerular filtration rate (eGFR) or kidney failure. Patients with lower podocyte density were predominantly male and had larger body surface area, greater proteinuria, fewer non-sclerotic glomeruli, larger glomeruli and higher single-nephron eGFR. During a median follow-up of 4.1 years, 18 (39%) patients reached endpoint. Kidney survival in patients with lower podocyte density was significantly worse than in patients with higher podocyte density. However, there was no difference in kidney survival between patient groups based on podocyte number per glomerulus. Cox hazard analysis showed that podocyte density, but not podocyte number per glomerulus, was associated with the kidney outcomes after adjustment for clinicopathological confounders. Thus, our study demonstrates that a relative depletion of podocytes better predicts long-term kidney outcomes than does absolute depletion of podocytes. Hence, the findings implicate mismatch between glomerular enlargement and podocyte number as a crucial determinant of disease progression in ORG.
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Affiliation(s)
- Kotaro Haruhara
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan; Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia.
| | - Yusuke Okabayashi
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Takaya Sasaki
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Eisuke Kubo
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Vivette D D'Agati
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA
| | - John F Bertram
- Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia; Australian Research Council Training Centre for Cell and Tissue Engineering Technologies, Brisbane, Australia
| | - Nobuo Tsuboi
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
| | - Takashi Yokoo
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
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19
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Lewko B, Wodzińska M, Daca A, Płoska A, Obremska K, Kalinowski L. Urolithin A Ameliorates the TGF Beta-Dependent Impairment of Podocytes Exposed to High Glucose. J Pers Med 2024; 14:914. [PMID: 39338168 PMCID: PMC11433157 DOI: 10.3390/jpm14090914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 08/10/2024] [Accepted: 08/14/2024] [Indexed: 09/30/2024] Open
Abstract
Increased activity of transforming growth factor-beta (TGF-β) is a key factor mediating kidney impairment in diabetes. Glomerular podocytes, the crucial component of the renal filter, are a direct target of TGF-β action, resulting in irreversible cell loss and progression of chronic kidney disease (CKD). Urolithin A (UA) is a member of the family of polyphenol metabolites produced by gut microbiota from ellagitannins and ellagic acid-rich foods. The broad spectrum of biological activities of UA makes it a promising candidate for the treatment of podocyte disorders. In this in vitro study, we investigated whether UA influences the changes exerted in podocytes by TGF-β and high glucose. Following a 7-day incubation in normal (NG, 5.5 mM) or high (HG, 25 mM) glucose, the cells were treated with UA and/or TGF-β1 for 24 h. HG and TGF-β1, each independent and in concert reduced expression of nephrin, increased podocyte motility, and up-regulated expression of b3 integrin and fibronectin. These typical-for-epithelial-to-mesenchymal transition (EMT) effects were inhibited by UA in both HG and NG conditions. UA also reduced the typically elevated HG expression of TGF-β receptors and activation of the TGF-β signal transducer Smad2. Our results indicate that in podocytes cultured in conditions mimicking the diabetic milieu, UA inhibits and reverses changes underlying podocytopenia in diabetic kidneys. Hence, UA should be considered as a potential therapeutic agent in podocytopathies.
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Affiliation(s)
- Barbara Lewko
- Department of Pharmaceutical Pathophysiology, Faculty of Pharmacy, Medical University of Gdansk, 80-210 Gdansk, Poland
| | | | - Agnieszka Daca
- Department of Physiopathology, Faculty of Medicine, Medical University of Gdansk, 80-210 Gdansk, Poland
| | - Agata Płoska
- Department of Medical Laboratory Diagnostics-Fahrenheit Biobank BBMRI, Faculty of Pharmacy, Medical University of Gdansk, 80-210 Gdansk, Poland
| | | | - Leszek Kalinowski
- Department of Medical Laboratory Diagnostics-Fahrenheit Biobank BBMRI, Faculty of Pharmacy, Medical University of Gdansk, 80-210 Gdansk, Poland
- BioTechMed Center, Department of Mechanics of Materials and Structures, Gdansk University of Technology, 80-223 Gdansk, Poland
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20
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de Cos M, Mosoyan G, Chauhan K, Troost JP, Wong JS, Lefferts S, Morgan P, Meliambro K, Egerman M, Ray J, Parker T, Levine D, Seshan S, Bardash Y, Horowitz B, Kent CA, Shaw MM, Perlman A, Moledina DG, Coca SG, Campbell KN. Urinary Plasminogen as a Marker of Disease Progression in Human Glomerular Disease. Am J Kidney Dis 2024; 84:205-214.e1. [PMID: 38452919 PMCID: PMC11260534 DOI: 10.1053/j.ajkd.2024.01.520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 12/27/2023] [Accepted: 01/12/2024] [Indexed: 03/09/2024]
Abstract
RATIONALE & OBJECTIVE Glomerular disorders have a highly variable clinical course, and biomarkers that reflect the molecular mechanisms underlying their progression are needed. Based on our previous work identifying plasminogen as a direct cause of podocyte injury, we designed this study to test the association between urine plasmin(ogen) (ie, plasmin and its precursor plasminogen) and end-stage kidney disease (ESKD). STUDY DESIGN Multicenter cohort study. SETTING & PARTICIPANTS 1,010 patients enrolled in the CureGN Cohort with biopsy-proven glomerular disease (focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A nephropathy). PREDICTORS The main predictor was urine plasmin(ogen) at baseline. Levels were measured by an electrochemiluminescent immunoassay developed de novo. Traditional clinical and analytical characteristics were used for adjustment. The ratio of urine plasmin(ogen)/expected plasmin(ogen) was evaluated as a predictor in a separate model. OUTCOME Progression to ESKD. ANALYTICAL APPROACH Cox regression was used to examine the association between urinary plasmin(ogen) and time to ESKD. Urinary markers were log2 transformed to approximate normal distribution and normalized to urinary creatinine (Log2uPlasminogen/cr, Log2 urinary protein/cr [UPCR]). Expected plasmin(ogen) was calculated by multiple linear regression. RESULTS Adjusted Log2uPlasminogen/cr was significantly associated with ESKD (HR per doubling Log2 uPlasminogen/cr 1.31 [95% CI, 1.22-1.40], P<0.001). Comparison of the predictive performance of the models including Log2 uPlasminogen/cr, Log2 UPCR, or both markers showed the plasmin(ogen) model superiority. The ratio of measured/expected urine plasmin(ogen) was independently associated with ESKD: HR, 0.41 (95% CI, 0.22-0.77) if ratio<0.8 and HR 2.42 (95% CI, 1.54-3.78) if ratio>1.1 (compared with ratio between 0.8 and 1.1). LIMITATIONS Single plasmin(ogen) determination does not allow for the study of changes over time. The use of a cohort of mostly white patients and the restriction to patients with 3 glomerular disorders limits the external validity of our analysis. CONCLUSIONS Urinary plasmin(ogen) and the ratio of measured/expected plasmin(ogen) are independently associated with ESKD in a cohort of patients with glomerular disease. Taken together with our previous experimental findings, urinary plasmin(ogen) could be a useful biomarker in prognostic decision making and a target for the development of novel therapies in patients with proteinuria and glomerular disease. PLAIN-LANGUAGE SUMMARY Glomerular diseases are an important cause of morbidity and mortality in patients of all ages. Knowing the individual risk of progression to dialysis or transplantation would help to plan the follow-up and treatment of these patients. Our work studies the usefulness of urinary plasminogen as a marker of progression in this context, since previous studies indicate that plasminogen may be involved in the mechanisms responsible for the progression of these disorders. Our work in a sample of 1,010 patients with glomerular disease demonstrates that urinary plasminogen (as well as the ratio of measured to expected plasminogen) is associated with the risk of progression to end-stage kidney disease. Urine plasminogen exhibited good performance and, if further validated, could enable risk stratification for timely interventions in patients with proteinuria and glomerular disease.
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Affiliation(s)
- Marina de Cos
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Gohar Mosoyan
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Kinsuk Chauhan
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jonathan P Troost
- Michigan Institute for Clinical and Health Research, University of Michigan, Ann Arbor, Michigan
| | - Jenny S Wong
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Sean Lefferts
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Paul Morgan
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Kristin Meliambro
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Marc Egerman
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Justina Ray
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Tom Parker
- Rogosin Institute, Weill Cornell Medicine, New York, New York
| | - Daniel Levine
- Rogosin Institute, Weill Cornell Medicine, New York, New York
| | - Surya Seshan
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
| | - Yoni Bardash
- St. Joseph's University Medical, Paterson, New Jersey
| | - Benjamin Horowitz
- Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey
| | - Candice A Kent
- Section of Nephrology and Clinical and Translational Research Accelerator, Department of Internal Medicine, School of Medicine, Yale University, New Haven, Connecticut
| | - Melissa M Shaw
- Section of Nephrology and Clinical and Translational Research Accelerator, Department of Internal Medicine, School of Medicine, Yale University, New Haven, Connecticut
| | - Alan Perlman
- Rogosin Institute, Weill Cornell Medicine, New York, New York; Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medicine, New York, New York
| | - Dennis G Moledina
- Section of Nephrology and Clinical and Translational Research Accelerator, Department of Internal Medicine, School of Medicine, Yale University, New Haven, Connecticut
| | - Steven G Coca
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Kirk N Campbell
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
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21
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Oulerich Z, Sferruzzi-Perri AN. Early-life exposures and long-term health: adverse gestational environments and the programming of offspring renal and vascular disease. Am J Physiol Renal Physiol 2024; 327:F21-F36. [PMID: 38695077 PMCID: PMC11687964 DOI: 10.1152/ajprenal.00383.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 03/25/2024] [Accepted: 03/26/2024] [Indexed: 06/21/2024] Open
Abstract
According to the Developmental Origins of Health and Disease hypothesis, exposure to certain environmental influences during early life may be a key determinant of fetal development and short- and long-term offspring health. Indeed, adverse conditions encountered during the fetal, perinatal, and early childhood stages can alter normal development and growth, as well as put the offspring at elevated risk of developing long-term health conditions in adulthood, including chronic kidney disease and cardiovascular diseases. Of relevance in understanding the mechanistic basis of these long-term health conditions are previous findings showing low glomerular number in human intrauterine growth restriction and low birth weight-indicators of a suboptimal intrauterine environment. In different animal models, the main suboptimal intrauterine conditions studied relate to maternal dietary manipulations, poor micronutrient intake, prenatal ethanol exposure, maternal diabetes, glucocorticoid and chemical exposure, hypoxia, and placental insufficiency. These studies have demonstrated changes in kidney structure, glomerular endowment, and expression of key genes and signaling pathways controlling endocrine, excretion, and filtration function of the offspring. This review aims to summarize those studies to uncover the effects and mechanisms by which adverse gestational environments impact offspring renal and vascular health in adulthood. This is important for identifying agents and interventions that can prevent and mitigate the long-term consequences of an adverse intrauterine environment on the subsequent generation.NEW & NOTEWORTHY Human data and experimental animal data show that suboptimal environments during fetal development increase the risk of renal and vascular diseases in adult-life. This is related to permanent changes in kidney structure, function, and expression of genes and signaling pathways controlling filtration, excretion, and endocrine function. Uncovering the mechanisms by which offspring renal development and function is impacted is important for identifying ways to mitigate the development of diseases that strain health care services worldwide.
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Affiliation(s)
- Zoé Oulerich
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
- Agro Paris Tech, Université Paris-Saclay, Paris, France
| | - Amanda N Sferruzzi-Perri
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
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22
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Chan H, Ni F, Zhao B, Jiang H, Ding J, Wang L, Wang X, Cui J, Feng S, Gao X, Yang X, Chi H, Lee H, Chen X, Li X, Jiao J, Wu D, Zhang G, Wang M, Cun Y, Ruan X, Yang H, Li Q. A genomic association study revealing subphenotypes of childhood steroid-sensitive nephrotic syndrome in a larger genomic sequencing cohort. Genes Dis 2024; 11:101126. [PMID: 38560502 PMCID: PMC10978544 DOI: 10.1016/j.gendis.2023.101126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 08/03/2023] [Accepted: 08/21/2023] [Indexed: 04/04/2024] Open
Abstract
Dissecting the genetic components that contribute to the two main subphenotypes of steroid-sensitive nephrotic syndrome (SSNS) using genome-wide association studies (GWAS) strategy is important for understanding the disease. We conducted a multicenter cohort study (360 patients and 1835 controls) combined with a GWAS strategy to identify susceptibility variants associated with the following two subphenotypes of SSNS: steroid-sensitive nephrotic syndrome without relapse (SSNSWR, 181 patients) and steroid-dependent/frequent relapse nephrotic syndrome (SDNS/FRNS, 179 patients). The distribution of two single-nucleotide polymorphisms (SNPs) in ANKRD36 and ALPG was significant between SSNSWR and healthy controls, and that of two SNPs in GAD1 and HLA-DQA1 was significant between SDNS/FRNS and healthy controls. Interestingly, rs1047989 in HLA-DQA1 was a candidate locus for SDNS/FRNS but not for SSNSWR. No significant SNPs were observed between SSNSWR and SDNS/FRNS. Meanwhile, chromosome 2:171713702 in GAD1 was associated with a greater steroid dose (>0.75 mg/kg/d) upon relapse to first remission in patients with SDNS/FRNS (odds ratio = 3.14; 95% confidence interval, 0.97-9.87; P = 0.034). rs117014418 in APOL4 was significantly associated with a decrease in eGFR of greater than 20% compared with the baseline in SDNS/FRNS patients (P = 0.0001). Protein-protein intersection network construction suggested that HLA-DQA1 and HLA-DQB1 function together through GSDMA. Thus, SSNSWR belongs to non-HLA region-dependent nephropathy, and the HLA-DQA/DQB region is likely strongly associated with disease relapse, especially in SDNS/FRNS. The study provides a novel approach for the GWAS strategy of SSNS and contributes to our understanding of the pathological mechanisms of SSNSWR and SDNS/FRNS.
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Affiliation(s)
- Han Chan
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China
| | - Fenfen Ni
- Department of Nephrology, Shenzhen Children's Hospital, Shenzhen, Guangdong 518034, China
| | - Bo Zhao
- Department of Nephrology, Kunming Children's Hospital, Kunming Medical University, Kunming, Yunnan 650228, China
| | - Huimin Jiang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China
| | - Juanjuan Ding
- Department of Nephrology, Wuhan Children's Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430015, China
| | - Li Wang
- Department of Nephrology, Chengdu Women and Children Central Hospital, Chengdu, Sichuan 610073, China
| | - Xiaowen Wang
- Department of Nephrology, Wuhan Children's Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430015, China
| | - Jingjing Cui
- Department of Nephrology, Kunming Children's Hospital, Kunming Medical University, Kunming, Yunnan 650228, China
| | - Shipin Feng
- Department of Nephrology, Chengdu Women and Children Central Hospital, Chengdu, Sichuan 610073, China
| | - Xiaojie Gao
- Department of Nephrology, Shenzhen Children's Hospital, Shenzhen, Guangdong 518034, China
| | - Xueying Yang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China
| | - Huan Chi
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China
| | - Hao Lee
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China
| | - Xuelan Chen
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China
| | - Xiaoqin Li
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China
| | - Jia Jiao
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China
| | - Daoqi Wu
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China
| | - Gaofu Zhang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China
| | - Mo Wang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China
| | - Yupeng Cun
- Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Xiongzhong Ruan
- Department of Nephrology, John Moorhead Research Laboratory, University College London Medical School, Royal Free Campus, University College London, London NW3 2PF, United Kingdom
| | - Haiping Yang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China
| | - Qiu Li
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China
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23
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Zheng Q, Zhao J, Yuan J, Qin Y, Zhu Z, Liu J, Sun S. Delaying Renal Aging: Metformin Holds Promise as a Potential Treatment. Aging Dis 2024; 16:1397-1413. [PMID: 39012670 PMCID: PMC12096913 DOI: 10.14336/ad.2024.0168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 06/06/2024] [Indexed: 07/17/2024] Open
Abstract
Given the rapid aging of the population, age-related diseases have become an excessive burden on global health care. The kidney, a crucial metabolic organ, ages relatively quickly. While the aging process itself does not directly cause kidney damage, the physiological changes that accompany it can impair the kidney's capacity for self-repair. This makes aging kidneys more susceptible to diseases, including increased risks of chronic kidney disease and end-stage renal disease. Therefore, delaying the progression of renal aging and preserving the youthful vitality of the kidney are crucial for preventing kidney diseases. However, effective strategies against renal aging are still lacking due to the underlying mechanisms of renal aging, which have not been fully elucidated. Accumulating evidence suggests that metformin has beneficial effects in mitigating renal aging. Metformin has shown promising anti-aging results in animal models but has not been tested for this purpose yet in clinical trials. These findings indicate the potential of metformin as an anti-renal aging drug. In this review, we primarily discuss the characteristics and mechanisms of kidney aging and the potential effects of metformin against renal aging.
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Affiliation(s)
- Qiao Zheng
- Department of Postgraduate Student, Xi’an Medical University, Xi’an, China
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Jin Zhao
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Jinguo Yuan
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Yunlong Qin
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Zhanxin Zhu
- Department of Postgraduate Student, Xi’an Medical University, Xi’an, China
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Jie Liu
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Shiren Sun
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
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24
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Fukuda A, Sato Y, Shibata H, Fujimoto S, Wiggins RC. Urinary podocyte markers of disease activity, therapeutic efficacy, and long-term outcomes in acute and chronic kidney diseases. Clin Exp Nephrol 2024; 28:496-504. [PMID: 38402504 PMCID: PMC11116200 DOI: 10.1007/s10157-024-02465-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 01/14/2024] [Indexed: 02/26/2024]
Abstract
A critical degree of podocyte depletion causes glomerulosclerosis, and persistent podocyte loss in glomerular diseases drives the progression to end-stage kidney disease. The extent of podocyte injury at a point in time can be histologically assessed by measuring podocyte number, size, and density ("Biopsy podometrics"). However, repeated invasive renal biopsies are associated with increased risk and cost. A noninvasive method for assessing podocyte injury and depletion is required. Albuminuria and proteinuria do not always correlate with disease activity. Podocytes are located on the urinary space side of the glomerular basement membrane, and as they undergo stress or detach, their products can be identified in urine. This raises the possibility that urinary podocyte products can serve as clinically useful markers for monitoring glomerular disease activity and progression ("Urinary podometrics"). We previously reported that urinary sediment podocyte mRNA reflects disease activity in both animal models and human glomerular diseases. This includes diabetes and hypertension which together account for 60% of new-onset dialysis induction patients. Improving approaches to preventing progression is an urgent priority for the renal community. Sufficient evidence now exists to indicate that monitoring urinary podocyte markers could serve as a useful adjunctive strategy for determining the level of current disease activity and response to therapy in progressive glomerular diseases.
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Affiliation(s)
- Akihiro Fukuda
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-Machi, Yufu City, Oita, 879-5593, Japan.
| | - Yuji Sato
- Division of Nephrology, Department of Internal Medicine, National Health Insurance Takachiho Town Hospital, Takachiho, Miyazaki, Japan
| | - Hirotaka Shibata
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-Machi, Yufu City, Oita, 879-5593, Japan
| | - Shouichi Fujimoto
- Department of Medical Environment Innovation, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Roger C Wiggins
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
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25
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Bărar AA, Pralea IE, Maslyennikov Y, Munteanu R, Berindan-Neagoe I, Pîrlog R, Rusu I, Nuțu A, Rusu CC, Moldovan DT, Potra AR, Tirinescu D, Ticala M, Elec FI, Iuga CA, Kacso IM. Minimal Change Disease: Pathogenetic Insights from Glomerular Proteomics. Int J Mol Sci 2024; 25:5613. [PMID: 38891801 PMCID: PMC11171934 DOI: 10.3390/ijms25115613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 05/13/2024] [Accepted: 05/15/2024] [Indexed: 06/21/2024] Open
Abstract
The mechanism underlying podocyte dysfunction in minimal change disease (MCD) remains unknown. This study aimed to shed light on the potential pathophysiology of MCD using glomerular proteomic analysis. Shotgun proteomics using label-free quantitative mass spectrometry was performed on formalin-fixed, paraffin-embedded (FFPE) renal biopsies from two groups of samples: control (CTR) and MCD. Glomeruli were excised from FFPE renal biopsies using laser capture microdissection (LCM), and a single-pot solid-phase-enhanced sample preparation (SP3) digestion method was used to improve yield and protein identifications. Principal component analysis (PCA) revealed a distinct separation between the CTR and MCD groups. Forty-eight proteins with different abundance between the two groups (p-value ≤ 0.05 and |FC| ≥ 1.5) were identified. These may represent differences in podocyte structure, as well as changes in endothelial or mesangial cells and extracellular matrix, and some were indeed found in several of these structures. However, most differentially expressed proteins were linked to the podocyte cytoskeleton and its dynamics. Some of these proteins are known to be involved in focal adhesion (NID1 and ITGA3) or slit diaphragm signaling (ANXA2, TJP1 and MYO1C), while others are structural components of the actin and microtubule cytoskeleton of podocytes (ACTR3 and NES). This study suggests the potential of mass spectrometry-based shotgun proteomic analysis with LCM glomeruli to yield valuable insights into the pathogenesis of podocytopathies like MCD. The most significantly dysregulated proteins in MCD could be attributable to cytoskeleton dysfunction or may be a compensatory response to cytoskeleton malfunction caused by various triggers.
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Affiliation(s)
- Andrada Alina Bărar
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.A.B.); (Y.M.); (C.C.R.); (D.T.M.); (A.R.P.); (D.T.); (M.T.); (I.M.K.)
| | - Ioana-Ecaterina Pralea
- Department of Proteomics and Metabolomics, Research Center for Advanced Medicine–MedFuture, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, Louis Pasteur Street 4-6, 400349 Cluj-Napoca, Romania;
| | - Yuriy Maslyennikov
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.A.B.); (Y.M.); (C.C.R.); (D.T.M.); (A.R.P.); (D.T.); (M.T.); (I.M.K.)
| | - Raluca Munteanu
- Department of In Vivo Studies, Research Center for Advanced Medicine–MedFuture, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, Louis Pasteur Street 6, 400349 Cluj-Napoca, Romania;
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; (I.B.-N.); (R.P.); (A.N.)
| | - Radu Pîrlog
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; (I.B.-N.); (R.P.); (A.N.)
| | - Ioana Rusu
- Department of Pathology, Regional Institute of Gastroenterology and Hepatology, 400394 Cluj-Napoca, Romania;
| | - Andreea Nuțu
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; (I.B.-N.); (R.P.); (A.N.)
| | - Crina Claudia Rusu
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.A.B.); (Y.M.); (C.C.R.); (D.T.M.); (A.R.P.); (D.T.); (M.T.); (I.M.K.)
| | - Diana Tania Moldovan
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.A.B.); (Y.M.); (C.C.R.); (D.T.M.); (A.R.P.); (D.T.); (M.T.); (I.M.K.)
| | - Alina Ramona Potra
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.A.B.); (Y.M.); (C.C.R.); (D.T.M.); (A.R.P.); (D.T.); (M.T.); (I.M.K.)
| | - Dacian Tirinescu
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.A.B.); (Y.M.); (C.C.R.); (D.T.M.); (A.R.P.); (D.T.); (M.T.); (I.M.K.)
| | - Maria Ticala
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.A.B.); (Y.M.); (C.C.R.); (D.T.M.); (A.R.P.); (D.T.); (M.T.); (I.M.K.)
| | - Florin Ioan Elec
- Department of Urology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Cristina Adela Iuga
- Department of Proteomics and Metabolomics, Research Center for Advanced Medicine–MedFuture, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, Louis Pasteur Street 4-6, 400349 Cluj-Napoca, Romania;
- Department of Pharmaceutical Analysis, Faculty of Pharmacy, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Ina Maria Kacso
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.A.B.); (Y.M.); (C.C.R.); (D.T.M.); (A.R.P.); (D.T.); (M.T.); (I.M.K.)
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Badeńska M, Pac M, Badeński A, Rutkowska K, Czubilińska-Łada J, Płoski R, Bohynikova N, Szczepańska M. A Rare De Novo Mutation in the TRIM8 Gene in a 17-Year-Old Boy with Steroid-Resistant Nephrotic Syndrome: Case Report. Int J Mol Sci 2024; 25:4486. [PMID: 38674071 PMCID: PMC11050435 DOI: 10.3390/ijms25084486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 04/12/2024] [Accepted: 04/17/2024] [Indexed: 04/28/2024] Open
Abstract
Idiopathic nephrotic syndrome is the most common chronic glomerular disease in children. Treatment with steroids is usually successful; however, in a small percentage of patients, steroid resistance is observed. The most frequent histologic kidney feature of steroid-resistant nephrotic syndrome (SRNS) is focal segmental glomerulosclerosis (FSGS). Genetic testing has become a valuable diagnostic tool in defining the etiology of SRNS, leading to the identification of a genetic cause. The TRIM8 gene is expressed in various tissues, including kidney cells and the central nervous system (CNS). An association between a mutation in the TRIM8 gene and an early onset of FSGS has been proposed but is not well described. We present a 17-year-old boy with epilepsy, early mild developmental delay, a low IgG serum level, and proteinuria, secondary to FSGS. A Next-Generation Sequencing (NGS)-based analysis revealed a heterozygous de novo pathogenic variant in the TRIM8 gene (c.1200C>G, p.Tyr400Ter). TRIM8 gene sequencing should be considered in individuals with early onset of FSGS, particularly accompanied by symptoms of cortical dysfunction, such as epilepsy and intellectual disability.
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Affiliation(s)
- Marta Badeńska
- Department of Pediatrics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, ul. 3 Maja 13/15, 41-800 Zabrze, Poland; (M.B.); (A.B.)
| | - Małgorzata Pac
- Department of Immunology, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland; (M.P.); (N.B.)
| | - Andrzej Badeński
- Department of Pediatrics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, ul. 3 Maja 13/15, 41-800 Zabrze, Poland; (M.B.); (A.B.)
| | - Karolina Rutkowska
- Department of Medical Genetics, Medical University of Warsaw, 02-106 Warsaw, Poland; (K.R.); (R.P.)
| | - Justyna Czubilińska-Łada
- Department of Neonatal Intensive Care and Neonatal Pathology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, ul. 3 Maja 13/15, 41-800 Zabrze, Poland;
| | - Rafał Płoski
- Department of Medical Genetics, Medical University of Warsaw, 02-106 Warsaw, Poland; (K.R.); (R.P.)
| | - Nadezda Bohynikova
- Department of Immunology, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland; (M.P.); (N.B.)
| | - Maria Szczepańska
- Department of Pediatrics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, ul. 3 Maja 13/15, 41-800 Zabrze, Poland; (M.B.); (A.B.)
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Li Y, Xu C, Zhao F, Liu Q, Qiu X, Li M, Yang Y, Yu S, Tong H, Zhang L, Chen B, Qu L, Yu Z. Podocyte-specific Nup160 knockout mice develop nephrotic syndrome and glomerulosclerosis. Hum Mol Genet 2024; 33:667-676. [PMID: 38224683 DOI: 10.1093/hmg/ddad211] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 12/15/2023] [Accepted: 12/18/2023] [Indexed: 01/17/2024] Open
Abstract
More than 60 monogenic genes mutated in steroid-resistant nephrotic syndrome (SRNS) have been identified. Our previous study found that mutations in nucleoporin 160 kD (NUP160) are implicated in SRNS. The NUP160 gene encodes a component of the nuclear pore complex. Recently, two siblings with homozygous NUP160 mutations presented with SRNS and a nervous system disorder. However, replication of nephrotic syndrome (NS)-associated phenotypes in a mammalian model following loss of Nup160 is needed to prove that NUP160 mutations cause SRNS. Here, we generated a podocyte-specific Nup160 knockout (Nup160podKO) mouse model using CRISPR/Cas9 and Cre/loxP technologies. We investigated NS-associated phenotypes in these Nup160podKO mice. We verified efficient abrogation of Nup160 in Nup160podKO mice at both the DNA and protein levels. We showed that Nup160podKO mice develop typical signs of NS. Nup160podKO mice exhibited progression of proteinuria to average albumin/creatinine ratio (ACR) levels of 15.06 ± 2.71 mg/mg at 26 weeks, and had lower serum albumin levels of 13.13 ± 1.34 g/l at 30 weeks. Littermate control mice had urinary ACR mean values of 0.03 mg/mg and serum albumin values of 22.89 ± 0.34 g/l at the corresponding ages. Further, Nup160podKO mice exhibited glomerulosclerosis compared with littermate control mice. Podocyte-specific Nup160 knockout in mice led to NS and glomerulosclerosis. Thus, our findings strongly support that mutations in NUP160 cause SRNS. The newly generated Nup160podKO mice are a reliable mammalian model for future study of the pathogenesis of NUP160-associated SRNS.
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Affiliation(s)
- Yuanyuan Li
- College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Maternity and Child Health Hospital, 18 Daoshan Road, Fuzhou, Fujian 350000, China
- College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Department of Nephrology, Rheumatology and Immunology, Fujian Children's Hospital, 966 Heng Yu Road, Fuzhou, Fujian 350014, China
- Fujian Key Laboratory of Women and Children's Critical Diseases Research, 18 Daoshan Road, Fuzhou, Fujian 350000, China
| | - Chan Xu
- College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Maternity and Child Health Hospital, 18 Daoshan Road, Fuzhou, Fujian 350000, China
- College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Department of Nephrology, Rheumatology and Immunology, Fujian Children's Hospital, 966 Heng Yu Road, Fuzhou, Fujian 350014, China
- Fujian Key Laboratory of Women and Children's Critical Diseases Research, 18 Daoshan Road, Fuzhou, Fujian 350000, China
- Department of Pediatrics, Fuzong Clinical Medical College, Fujian Medical University, 156 Xi Er Huan Bei Road, Fuzhou, Fujian 350025, China
| | - Feng Zhao
- College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Department of Nephrology, Rheumatology and Immunology, Fujian Children's Hospital, 966 Heng Yu Road, Fuzhou, Fujian 350014, China
| | - Qinghong Liu
- Department of Pathology, Fuzong Clinical Medical College, Fujian Medical University, 156 Xi Er Huan Bei Road, Fuzhou, Fujian 350025, China
| | - Xiaojian Qiu
- College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Department of Nephrology, Rheumatology and Immunology, Fujian Children's Hospital, 966 Heng Yu Road, Fuzhou, Fujian 350014, China
| | - Min Li
- Department of Pathology, Fuzong Clinical Medical College, Fujian Medical University, 156 Xi Er Huan Bei Road, Fuzhou, Fujian 350025, China
| | - Yonghui Yang
- College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Department of Nephrology, Rheumatology and Immunology, Fujian Children's Hospital, 966 Heng Yu Road, Fuzhou, Fujian 350014, China
| | - Shentong Yu
- Department of Pathology, Fuzong Clinical Medical College, Fujian Medical University, 156 Xi Er Huan Bei Road, Fuzhou, Fujian 350025, China
| | - Huajuan Tong
- College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Department of Nephrology, Rheumatology and Immunology, Fujian Children's Hospital, 966 Heng Yu Road, Fuzhou, Fujian 350014, China
| | - Lifang Zhang
- Department of Pathology, Fuzong Clinical Medical College, Fujian Medical University, 156 Xi Er Huan Bei Road, Fuzhou, Fujian 350025, China
| | - Bing Chen
- College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Department of Nephrology, Rheumatology and Immunology, Fujian Children's Hospital, 966 Heng Yu Road, Fuzhou, Fujian 350014, China
| | - Lijuan Qu
- Department of Pathology, Fuzong Clinical Medical College, Fujian Medical University, 156 Xi Er Huan Bei Road, Fuzhou, Fujian 350025, China
| | - Zihua Yu
- College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Maternity and Child Health Hospital, 18 Daoshan Road, Fuzhou, Fujian 350000, China
- College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Department of Nephrology, Rheumatology and Immunology, Fujian Children's Hospital, 966 Heng Yu Road, Fuzhou, Fujian 350014, China
- Fujian Key Laboratory of Women and Children's Critical Diseases Research, 18 Daoshan Road, Fuzhou, Fujian 350000, China
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Buerger F, Salmanullah D, Liang L, Gauntner V, Krueger K, Qi M, Sharma V, Rubin A, Ball D, Lemberg K, Saida K, Merz LM, Sever S, Issac B, Sun L, Guerrero-Castillo S, Gomez AC, McNulty MT, Sampson MG, Al-Hamed MH, Saleh MM, Shalaby M, Kari J, Fawcett JP, Hildebrandt F, Majmundar AJ. Recessive variants in the intergenic NOS1AP-C1orf226 locus cause monogenic kidney disease responsive to anti-proteinuric treatment. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.03.17.24303374. [PMID: 38562757 PMCID: PMC10984069 DOI: 10.1101/2024.03.17.24303374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
In genetic disease, an accurate expression landscape of disease genes and faithful animal models will enable precise genetic diagnoses and therapeutic discoveries, respectively. We previously discovered that variants in NOS1AP , encoding nitric oxide synthase 1 (NOS1) adaptor protein, cause monogenic nephrotic syndrome (NS). Here, we determined that an intergenic splice product of N OS1AP / Nos1ap and neighboring C1orf226/Gm7694 , which precludes NOS1 binding, is the predominant isoform in mammalian kidney transcriptional and proteomic data. Gm7694 -/- mice, whose allele exclusively disrupts the intergenic product, developed NS phenotypes. In two human NS subjects, we identified causative NOS1AP splice variants, including one predicted to abrogate intergenic splicing but initially misclassified as benign based on the canonical transcript. Finally, by modifying genetic background, we generated a faithful mouse model of NOS1AP -associated NS, which responded to anti-proteinuric treatment. This study highlights the importance of intergenic splicing and a potential treatment avenue in a mendelian disorder.
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de Zoysa N, Haruhara K, Nikolic-Paterson DJ, Kerr PG, Ling J, Gazzard SE, Puelles VG, Bertram JF, Cullen-McEwen LA. Podocyte number and glomerulosclerosis indices are associated with the response to therapy for primary focal segmental glomerulosclerosis. Front Med (Lausanne) 2024; 11:1343161. [PMID: 38510448 PMCID: PMC10951056 DOI: 10.3389/fmed.2024.1343161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 02/19/2024] [Indexed: 03/22/2024] Open
Abstract
Corticosteroid therapy, often in combination with inhibition of the renin-angiotensin system, is first-line therapy for primary focal and segmental glomerulosclerosis (FSGS) with nephrotic-range proteinuria. However, the response to treatment is variable, and therefore new approaches to indicate the response to therapy are required. Podocyte depletion is a hallmark of early FSGS, and here we investigated whether podocyte number, density and/or size in diagnostic biopsies and/or the degree of glomerulosclerosis could indicate the clinical response to first-line therapy. In this retrospective single center cohort study, 19 participants (13 responders, 6 non-responders) were included. Biopsies obtained at diagnosis were prepared for analysis of podocyte number, density and size using design-based stereology. Renal function and proteinuria were assessed 6 months after therapy commenced. Responders and non-responders had similar levels of proteinuria at the time of biopsy and similar kidney function. Patients who did not respond to treatment at 6 months had a significantly higher percentage of glomeruli with global sclerosis than responders (p < 0.05) and glomerulosclerotic index (p < 0.05). Podocyte number per glomerulus in responders was 279 (203-507; median, IQR), 50% greater than that of non-responders (186, 118-310; p < 0.05). These findings suggest that primary FSGS patients with higher podocyte number per glomerulus and less advanced glomerulosclerosis are more likely to respond to first-line therapy at 6 months. A podocyte number less than approximately 216 per glomerulus, a GSI greater than 1 and percentage global sclerosis greater than approximately 20% are associated with a lack of response to therapy. Larger, prospective studies are warranted to confirm whether these parameters may help inform therapeutic decision making at the time of diagnosis of primary FSGS.
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Affiliation(s)
- Natasha de Zoysa
- Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
| | - Kotaro Haruhara
- Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
- Division of Nephrology and Hypertension, Jikei University School of Medicine, Tokyo, Japan
| | - David J. Nikolic-Paterson
- Department of Nephrology, Monash Medical Centre, Clayton, VIC, Australia
- Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC, Australia
| | - Peter G. Kerr
- Department of Nephrology, Monash Medical Centre, Clayton, VIC, Australia
- Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC, Australia
| | - Jonathan Ling
- Department of Nephrology, Monash Medical Centre, Clayton, VIC, Australia
- Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC, Australia
| | - Sarah E. Gazzard
- Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
| | - Victor G. Puelles
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
| | - John F. Bertram
- Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
- ARC Training Centre for Cell and Tissue Engineering Technologies, Melbourne, VIC, Australia
- ARC Training Centre for Cell and Tissue Engineering Technologies, Brisbane, QLD, Australia
| | - Luise A. Cullen-McEwen
- Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
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Garnier AS, Laubacher H, Briet M. Drug-induced glomerular diseases. Therapie 2024; 79:271-281. [PMID: 37973491 DOI: 10.1016/j.therap.2023.10.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 09/18/2023] [Indexed: 11/19/2023]
Abstract
Drug-induced kidney diseases represent a wide range of diseases that are responsible for a significant proportion of all acute kidney injuries and chronic kidney diseases. In the present review, we focused on drug-induced glomerular diseases, more precisely podocytopathies - minimal change diseases (MCD), focal segmental glomerulosclerosis (FSGS) - and membranous nephropathies (MN), from a physiological and a pharmacological point of view. The glomerular filtration barrier is composed of podocytes that form foot processes tightly connected and directly in contact with the basal membrane and surrounding capillaries. The common clinical feature of these diseases is represented by the loss of the ability of the filtration barrier to retain large proteins, leading to massive proteinuria and nephrotic syndrome. Drugs such as non-steroidal anti-inflammatory drugs (NSAIDs), D-penicillamine, tiopronin, trace elements, bisphosphonate, and interferons have been historically associated with the occurrence of MCD, FSGS, and MN. In the last ten years, the development of new anti-cancer agents, including tyrosine kinase inhibitors and immune checkpoint inhibitors, and research into their renal adverse effects highlighted these issues and have improved our comprehension of these diseases.
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Affiliation(s)
- Anne-Sophie Garnier
- Service de néphrologie-dialyse-transplantation, CHU d'Angers, 49000 Angers, France; UFR Santé, université d'Angers, 49000 Angers, France; Université d'Angers, UMR CNRS 6015, Inserm U1083, unité MitoVasc, Team Carme, SFR ICAT, 49000 Angers, France; Laboratoire MitoVasc, UMR Inserm 1083 CNRS 6215, 49000 Angers, France
| | - Hélène Laubacher
- UFR Santé, université d'Angers, 49000 Angers, France; Laboratoire MitoVasc, UMR Inserm 1083 CNRS 6215, 49000 Angers, France
| | - Marie Briet
- UFR Santé, université d'Angers, 49000 Angers, France; Université d'Angers, UMR CNRS 6015, Inserm U1083, unité MitoVasc, Team Carme, SFR ICAT, 49000 Angers, France; Laboratoire MitoVasc, UMR Inserm 1083 CNRS 6215, 49000 Angers, France; Service de pharmacologie - toxicologie et pharmacovigilance, CHU d'Angers, 49000 Angers, France.
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Yu Y, Hu G, Yang X, Yin Y, Tong K, Yu R. A strategic study of acupuncture for diabetic kidney disease based on meta-analysis and data mining. Front Endocrinol (Lausanne) 2024; 15:1273265. [PMID: 38469137 PMCID: PMC10925656 DOI: 10.3389/fendo.2024.1273265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 01/22/2024] [Indexed: 03/13/2024] Open
Abstract
Objective The specific benefit and selection of acupoints in acupuncture for diabetic kidney disease (DKD) remains controversial. This study aims to explore the specific benefits and acupoints selection of acupuncture for DKD through meta-analysis and data mining. Methods Clinical trials of acupuncture for DKD were searched in eight common databases. Meta-analysis was used to evaluate its efficacy and safety, and data mining was used to explore its acupoints selection. Results Meta-analysis displayed that compared with the conventional drug group, the combined acupuncture group significantly increased the clinical effective rate (risk ratio [RR] 1.35, 95% confidence interval [CI] 1.20 to 1.51, P < 0.00001) and high-density lipoprotein cholesterol (mean difference [MD] 0.36, 95% CI 0.27 to 0.46, P < 0.00001), significantly reduced the urinary albumin (MD -0.39, 95% CI -0.42 to -0.36, P < 0.00001), urinary microalbumin (MD -32.63, 95% CI -42.47 to -22.79, P < 0.00001), urine β2-microglobulin (MD -0.45, 95% CI -0.66 to -0.24, P < 0.0001), serum creatinine (MD -15.36, 95% CI -21.69 to -9.03, P < 0.00001), glycated hemoglobin A1c (MD -0.69, 95% CI -1.18 to -0.19, P = 0.006), fasting blood glucose (MD -0.86, 95% CI -0.90 to -0.82, P < 0.00001), 2h postprandial plasma glucose (MD -0.87, 95% CI -0.92 to -0.82, P < 0.00001), total cholesterol (MD -1.23, 95% CI -2.05 to -0.40, P = 0.003), triglyceride (MD -0.69, 95% CI -1.23 to -0.15, P = 0.01), while adverse events were comparable. Data mining revealed that CV12, SP8, SP10, ST36, SP6, BL20, BL23, and SP9 were the core acupoints for DKD treated by acupuncture. Conclusion Acupuncture improved clinical symptoms, renal function indices such as uALB, umALB, uβ2-MG, and SCR, as well as blood glucose and blood lipid in patients with DKD, and has a favorable safety profile. CV12, SP8, SP10, ST36, SP6, BL20, BL23, and SP9 are the core acupoints for acupuncture in DKD, and this program is expected to become a supplementary treatment for DKD.
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Affiliation(s)
- Yunfeng Yu
- Department of Endocrinology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Gang Hu
- Department of Endocrinology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Xinyu Yang
- College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Yuman Yin
- College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Keke Tong
- Department of Gastroenterology, The Hospital of Hunan University of Traditional Chinese Medicine, Changde, Hunan, China
| | - Rong Yu
- Department of Endocrinology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
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Pantel D, Mertens ND, Schneider R, Hölzel S, Kari JA, Desoky SE, Shalaby MA, Lim TY, Sanna-Cherchi S, Shril S, Hildebrandt F. Copy number variation analysis in 138 families with steroid-resistant nephrotic syndrome identifies causal homozygous deletions in PLCE1 and NPHS2 in two families. Pediatr Nephrol 2024; 39:455-461. [PMID: 37670083 PMCID: PMC10979458 DOI: 10.1007/s00467-023-06134-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 07/06/2023] [Accepted: 08/10/2023] [Indexed: 09/07/2023]
Abstract
BACKGROUND Steroid-resistant nephrotic syndrome (SRNS) is the second most common cause of kidney failure in children and adults under the age of 20 years. Previously, we were able to detect by exome sequencing (ES) a known monogenic cause of SRNS in 25-30% of affected families. However, ES falls short of detecting copy number variants (CNV). Therefore, we hypothesized that causal CNVs could be detected in a large SRNS cohort. METHODS We performed genome-wide single nucleotide polymorphism (SNP)-based CNV analysis on a cohort of 138 SRNS families, in whom we previously did not identify a genetic cause through ES. We evaluated ES and CNV data for variants in 60 known SRNS genes and in 13 genes in which variants are known to cause a phenocopy of SRNS. We applied previously published, predefined criteria for CNV evaluation. RESULTS We detected a novel CNV in two genes in 2 out of 138 families (1.5%). The 9,673 bp homozygous deletion in PLCE1 and the 6,790 bp homozygous deletion in NPHS2 were confirmed across the breakpoints by PCR and Sanger sequencing. CONCLUSIONS We confirmed that CNV analysis can identify the genetic cause in SRNS families that remained unsolved after ES. Though the rate of detected CNVs is minor, CNV analysis can be used when there are no other genetic causes identified. Causative CNVs are less common in SRNS than in other monogenic kidney diseases, such as congenital anomalies of the kidneys and urinary tract, where the detection rate was 5.3%. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Affiliation(s)
- Dalia Pantel
- Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
- Institute of Human Genetics, Heidelberg University, Heidelberg, Germany
| | - Nils D Mertens
- Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Ronen Schneider
- Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Selina Hölzel
- Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Jameela A Kari
- Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Pediatric Nephrology Center of Excellence, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
| | - Sherif El Desoky
- Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Pediatric Nephrology Center of Excellence, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
| | - Mohamed A Shalaby
- Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Pediatric Nephrology Center of Excellence, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
| | - Tze Y Lim
- Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA
| | - Simone Sanna-Cherchi
- Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA
| | - Shirlee Shril
- Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Friedhelm Hildebrandt
- Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA.
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Okabe M, Koike K, Yamamoto I, Tsuboi N, Matsusaka T, Yokoo T. Early growth response 1 as a podocyte injury marker in human glomerular diseases. Clin Kidney J 2024; 17:sfad289. [PMID: 38186896 PMCID: PMC10768762 DOI: 10.1093/ckj/sfad289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Indexed: 01/09/2024] Open
Abstract
Background In human glomerular diseases, visualizing podocyte injury is desirable since podocytes do not regenerate and podocyte injury leads to podocyte loss. Herein, we investigated the utility of immunostaining for early growth response 1 (EGR1), which is expressed in injured podocytes from the early stages of injury in animal experiments, as a podocyte injury marker in human glomerular diseases. Methods This study included 102 patients with biopsy-proven glomerular diseases between 2018 and 2021. The proportion of EGR1 expression in podocytes (%EGR1pod) was analyzed in relation to clinical and histopathological features, including glomerular and urinary podocyte-specific markers. Results %EGR1pod correlated significantly with the urinary protein:creatinine ratio, urinary nephrin and podocin mRNA levels, and glomerular podocin staining (rho = 0.361, 0.514, 0.487 and -0.417, respectively; adjusted P = .002, <.001, <.001 and <.001, respectively). Additionally, %EGR1pod correlated with cellular/fibrocellular crescents (rho = 0.479, adjusted P <.001). %EGR1pod was high in patients with glomerulonephritis, such as immunoglobulin A nephropathy (IgAN), lupus nephritis and antineutrophil cytoplasmic antibody-associated glomerulonephritis, and in those with podocytopathies, such as membranous nephropathy and primary focal segmental glomerulosclerosis, while %EGR1pod was low in patients with minimal change disease. In a subgroup analysis of IgAN, %EGR1pod was higher in Oxford C1 patients than in C0 patients. However, unexpectedly, patients with higher %EGR1pod were more prone to attain proteinuria remission, suggesting that EGR1 in the context of IgAN reflects reversible early injury. Conclusions Our findings indicate that EGR1 is a promising potential marker for identifying active early podocyte injury in human glomerular diseases.
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Affiliation(s)
- Masahiro Okabe
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Kentaro Koike
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Izumi Yamamoto
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Nobuo Tsuboi
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Taiji Matsusaka
- Departments of Basic Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Takashi Yokoo
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
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Klomp LS, Levtchenko E, Westland R. Developmental Causes of Focal Segmental Glomerulosclerosis. GLOMERULAR DISEASES 2024; 4:95-104. [PMID: 38952413 PMCID: PMC11216339 DOI: 10.1159/000538345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 03/08/2024] [Indexed: 07/03/2024]
Abstract
Background Focal segmental glomerulosclerosis (FSGS) is a histological pattern of glomerular damage that includes idiopathic conditions as well as genetic and non-genetic forms. Among these various etiologies, different phenotypes within the spectrum of congenital anomalies of the kidney and urinary tract (CAKUT) have been associated with FSGS. Summary Until recently, the main pathomechanism of how congenital kidney and urinary tract defects lead to FSGS was attributed to a reduced number of nephrons, resulting in biomechanical stress on the remaining glomeruli, detachment of podocytes, and subsequent inability to maintain normal glomerular architecture. The discovery of deleterious single-nucleotide variants in PAX2, a transcription factor crucial in normal kidney development and a known cause of papillorenal syndrome, in individuals with adult-onset FSGS without congenital kidney defects has shed new light on developmental defects that become evident during podocyte injury. Key Message In this mini-review, we challenge the assumption that FSGS in CAKUT is caused by glomerular hyperfiltration alone and hypothesize a multifactorial pathogenesis that includes overlapping cellular mechanisms that are activated in both damaged podocytes as well as nephron progenitor cells.
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Affiliation(s)
- Luna Shane Klomp
- Department of Pediatric Nephrology, Emma Children's Hospital - Amsterdam UMC, Location University of Amsterdam, Amsterdam, The Netherlands
| | - Elena Levtchenko
- Department of Pediatric Nephrology, Emma Children's Hospital - Amsterdam UMC, Location University of Amsterdam, Amsterdam, The Netherlands
| | - Rik Westland
- Department of Pediatric Nephrology, Emma Children's Hospital - Amsterdam UMC, Location University of Amsterdam, Amsterdam, The Netherlands
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Lindoso RS, Collino F, Kasai-Brunswick TH, Costa MR, Verdoorn KS, Einicker-Lamas M, Vieira-Beiral HJ, Wessely O, Vieyra A. Resident Stem Cells in Kidney Tissue. RESIDENT STEM CELLS AND REGENERATIVE THERAPY 2024:159-203. [DOI: 10.1016/b978-0-443-15289-4.00009-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Veloso Pereira BM, Zeng Y, Maggiore JC, Schweickart RA, Eng DG, Kaverina N, McKinzie SR, Chang A, Loretz CJ, Thieme K, Hukriede NA, Pippin JW, Wessely O, Shankland SJ. Podocyte injury at young age causes premature senescence and worsens glomerular aging. Am J Physiol Renal Physiol 2024; 326:F120-F134. [PMID: 37855038 PMCID: PMC11198990 DOI: 10.1152/ajprenal.00261.2023] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 10/10/2023] [Accepted: 10/10/2023] [Indexed: 10/20/2023] Open
Abstract
As life expectancy continues to rise, age-related diseases are becoming more prevalent. For example, proteinuric glomerular diseases typified by podocyte injury have worse outcomes in the elderly compared with young patients. However, the reasons are not well understood. We hypothesized that injury to nonaged podocytes induces senescence, which in turn augments their aging processes. In primary cultured human podocytes, injury induced by a cytopathic antipodocyte antibody, adriamycin, or puromycin aminonucleoside increased the senescence-related genes CDKN2A (p16INK4a/p14ARF), CDKN2D (p19INK4d), and CDKN1A (p21). Podocyte injury in human kidney organoids was accompanied by increased expression of CDKN2A, CDKN2D, and CDKN1A. In young mice, experimental focal segmental glomerulosclerosis (FSGS) induced by adriamycin and antipodocyte antibody increased the glomerular expression of p16, p21, and senescence-associated β-galactosidase (SA-β-gal). To assess the long-term effects of early podocyte injury-induced senescence, we temporally followed young mice with experimental FSGS through adulthood (12 m of age) and middle age (18 m of age). p16 and Sudan black staining were higher at middle age in mice with earlier FSGS compared with age-matched mice that did not get FSGS when young. This was accompanied by lower podocyte density, reduced canonical podocyte protein expression, and increased glomerular scarring. These results are consistent with injury-induced senescence in young podocytes, leading to increased senescence of podocytes by middle age accompanied by lower podocyte lifespan and health span.NEW & NOTEWORTHY Glomerular function is decreased by aging. However, little is known about the molecular mechanisms involved in age-related glomerular changes and which factors could contribute to a worse glomerular aging process. Here, we reported that podocyte injury in young mice and culture podocytes induced senescence, a marker of aging, and accelerates glomerular aging when compared with healthy aging mice.
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Affiliation(s)
- Beatriz Maria Veloso Pereira
- Division of Nephrology, University of Washington, Seattle, Washington, United States
- Department of Physiology and Biophysics, University of São Paulo, São Paulo, Brazil
| | - Yuting Zeng
- Department of Chemistry, University of Washington, Seattle, Washington, United States
| | - Joseph C Maggiore
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
| | | | - Diana G Eng
- Division of Nephrology, University of Washington, Seattle, Washington, United States
| | - Natalya Kaverina
- Division of Nephrology, University of Washington, Seattle, Washington, United States
| | - Sierra R McKinzie
- Division of Nephrology, University of Washington, Seattle, Washington, United States
| | - Anthony Chang
- Department of Pathology, University of Chicago, Chicago, Illinois, United States
| | - Carol J Loretz
- Division of Nephrology, University of Washington, Seattle, Washington, United States
| | - Karina Thieme
- Department of Physiology and Biophysics, University of São Paulo, São Paulo, Brazil
| | - Neil A Hukriede
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
| | - Jeffrey W Pippin
- Division of Nephrology, University of Washington, Seattle, Washington, United States
| | - Oliver Wessely
- Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States
| | - Stuart J Shankland
- Division of Nephrology, University of Washington, Seattle, Washington, United States
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States
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Sun Y, Jin D, Zhang Z, Ji H, An X, Zhang Y, Yang C, Sun W, Zhang Y, Duan Y, Kang X, Jiang L, Zhao X, Lian F. N6-methyladenosine (m6A) methylation in kidney diseases: Mechanisms and therapeutic potential. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2023; 1866:194967. [PMID: 37553065 DOI: 10.1016/j.bbagrm.2023.194967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 07/31/2023] [Accepted: 08/01/2023] [Indexed: 08/10/2023]
Abstract
The N6-methyladenosine (m6A) modification is regulated by methylases, commonly referred to as "writers," and demethylases, known as "erasers," leading to a dynamic and reversible process. Changes in m6A levels have been implicated in a wide range of cellular processes, including nuclear RNA export, mRNA metabolism, protein translation, and RNA splicing, establishing a strong correlation with various diseases. Both physiologically and pathologically, m6A methylation plays a critical role in the initiation and progression of kidney disease. The methylation of m6A may also facilitate the early diagnosis and treatment of kidney diseases, according to accumulating research. This review aims to provide a comprehensive overview of the potential role and mechanism of m6A methylation in kidney diseases, as well as its potential application in the treatment of such diseases. There will be a thorough examination of m6A methylation mechanisms, paying particular attention to the interplay between m6A writers, m6A erasers, and m6A readers. Furthermore, this paper will elucidate the interplay between various kidney diseases and m6A methylation, summarize the expression patterns of m6A in pathological kidney tissues, and discuss the potential therapeutic benefits of targeting m6A in the context of kidney diseases.
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Affiliation(s)
- Yuting Sun
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - De Jin
- Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, China
| | - Ziwei Zhang
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Hangyu Ji
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xuedong An
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yuehong Zhang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Cunqing Yang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wenjie Sun
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yuqing Zhang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yingying Duan
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaomin Kang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Linlin Jiang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xuefei Zhao
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Fengmei Lian
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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Schindler M, Siegerist F, Lange T, Simm S, Bach SM, Klawitter M, Gehrig J, Gul S, Endlich N. A Novel High-Content Screening Assay Identified Belinostat as Protective in a FSGS-Like Zebrafish Model. J Am Soc Nephrol 2023; 34:1977-1990. [PMID: 37752628 PMCID: PMC10703078 DOI: 10.1681/asn.0000000000000235] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 09/11/2023] [Indexed: 09/28/2023] Open
Abstract
BACKGROUND FSGS affects the complex three-dimensional morphology of podocytes, resulting in loss of filtration barrier function and the development of sclerotic lesions. Therapies to treat FSGS are limited, and podocyte-specific drugs are unavailable. To address the need for treatments to delay or stop FSGS progression, researchers are exploring the repurposing of drugs that have been approved by the US Food and Drug Administration (FDA) for other purposes. METHODS To identify drugs with potential to treat FSGS, we used a specific zebrafish screening strain to combine a high-content screening (HCS) approach with an in vivo model. This zebrafish screening strain expresses nitroreductase and the red fluorescent protein mCherry exclusively in podocytes (providing an indicator for podocyte depletion), as well as a circulating 78 kDa vitamin D-binding enhanced green fluorescent protein fusion protein (as a readout for proteinuria). To produce FSGS-like lesions in the zebrafish, we added 80 µ M metronidazole into the fish water. We used a specific screening microscope in conjunction with advanced image analysis methods to screen a library of 138 drugs and compounds (including some FDA-approved drugs) for podocyte-protective effects. Promising candidates were validated to be suitable for translational studies. RESULTS After establishing this novel in vivo HCS assay, we identified seven drugs or compounds that were protective in our FSGS-like model. Validation experiments confirmed that the FDA-approved drug belinostat was protective against larval FSGS. Similar pan-histone deacetylase inhibitors also showed potential to reproduce this effect. CONCLUSIONS Using an FSGS-like zebrafish model, we developed a novel in vivo HCS assay that identified belinostat and related pan-histone deacetylase inhibitors as potential candidates for treating FSGS.
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Affiliation(s)
- Maximilian Schindler
- Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
| | - Florian Siegerist
- Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
| | - Tim Lange
- Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
| | - Stefan Simm
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Hamburg, Germany
| | - Sophia-Marie Bach
- Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
| | - Marianne Klawitter
- Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
| | | | - Sheraz Gul
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Hamburg, Germany
- Fraunhofer Cluster of Excellence for Immune-Mediated Diseases CIMD, Hamburg, Germany
| | - Nicole Endlich
- Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
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Nguyen JK, Wu Z, Agudelo J, Herlitz LC, Miller AW, Bruggeman LA. Local Inflammation But Not Kidney Cell Infection Associated with High APOL1 Expression in COVID-Associated Nephropathy. KIDNEY360 2023; 4:1757-1762. [PMID: 37927001 PMCID: PMC10758510 DOI: 10.34067/kid.0000000000000290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 10/19/2023] [Indexed: 11/07/2023]
Abstract
In coronavirus disease-19 biopsies, detection of severe acute respiratory syndrome coronavirus 2 was rare with no evidence of viral replication, whereas autopsy tissue failed quality control. In patients with FSGS, apolipoprotein L1 expression differed by degree of immune cell infiltrates, with some podocytes exhibiting up to 18-fold higher expression. In COVAN, the predicted high induction of apolipoprotein L1 expression occurs in a pattern consistent with the stochastic nature of FSGS pathology.
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Affiliation(s)
- Jane K. Nguyen
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio
| | - Zhenzhen Wu
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio
| | - Jose Agudelo
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, Ohio
| | - Leal C. Herlitz
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio
| | - Aaron W. Miller
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, Ohio
- Department of Urology, Cleveland Clinic, Cleveland, Ohio
| | - Leslie A. Bruggeman
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio
- Department of Kidney Medicine, Cleveland Clinic, Cleveland, Ohio
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Sanchez-Niño MD, Ceballos MI, Carriazo S, Pintor-Chocano A, Sanz AB, Saleem MA, Ortiz A. Interaction of Fabry Disease and Diabetes Mellitus: Suboptimal Recruitment of Kidney Protective Factors. Int J Mol Sci 2023; 24:15853. [PMID: 37958836 PMCID: PMC10650640 DOI: 10.3390/ijms242115853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 10/27/2023] [Accepted: 10/29/2023] [Indexed: 11/15/2023] Open
Abstract
Fabry disease is a lysosomal disease characterized by globotriaosylceramide (Gb3) accumulation. It may coexist with diabetes mellitus and both cause potentially lethal kidney end-organ damage. However, there is little information on their interaction with kidney disease. We have addressed the interaction between Fabry disease and diabetes in data mining of human kidney transcriptomics databases and in Fabry (Gla-/-) and wild type mice with or without streptozotocin-induced diabetes. Data mining was consistent with differential expression of genes encoding enzymes from the Gb3 metabolic pathway in human diabetic kidney disease, including upregulation of UGCG, the gene encoding the upstream and rate-limiting enzyme glucosyl ceramide synthase. Diabetic Fabry mice displayed the most severe kidney infiltration by F4/80+ macrophages, and a lower kidney expression of kidney protective genes (Pgc1α and Tfeb) than diabetic wild type mice, without a further increase in kidney fibrosis. Moreover, only diabetic Fabry mice developed kidney insufficiency and these mice with kidney insufficiency had a high expression of Ugcg. In conclusion, we found evidence of interaction between diabetes and Fabry disease that may increase the severity of the kidney phenotype through modulation of the Gb3 synthesis pathway and downregulation of kidney protective genes.
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Affiliation(s)
- Maria D. Sanchez-Niño
- Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, 28040 Madrid, Spain; (M.I.C.); (S.C.); (A.P.-C.); (A.B.S.)
- RICORS2040, 28040 Madrid, Spain
- Department of Pharmacology, School of Medicine, Universidad Autonoma de Madrid, 28029 Madrid, Spain
| | - Maria I. Ceballos
- Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, 28040 Madrid, Spain; (M.I.C.); (S.C.); (A.P.-C.); (A.B.S.)
- RICORS2040, 28040 Madrid, Spain
| | - Sol Carriazo
- Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, 28040 Madrid, Spain; (M.I.C.); (S.C.); (A.P.-C.); (A.B.S.)
- RICORS2040, 28040 Madrid, Spain
| | - Aranzazu Pintor-Chocano
- Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, 28040 Madrid, Spain; (M.I.C.); (S.C.); (A.P.-C.); (A.B.S.)
- RICORS2040, 28040 Madrid, Spain
| | - Ana B. Sanz
- Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, 28040 Madrid, Spain; (M.I.C.); (S.C.); (A.P.-C.); (A.B.S.)
- RICORS2040, 28040 Madrid, Spain
| | - Moin A. Saleem
- Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1UD, UK;
| | - Alberto Ortiz
- Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, 28040 Madrid, Spain; (M.I.C.); (S.C.); (A.P.-C.); (A.B.S.)
- RICORS2040, 28040 Madrid, Spain
- Department of Medicine, School of Medicine, Universidad Autonoma de Madrid, 28029 Madrid, Spain
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Lizotte F, Rousseau M, Denhez B, Lévesque D, Guay A, Liu H, Moreau J, Higgins S, Sabbagh R, Susztak K, Boisvert FM, Côté AM, Geraldes P. Deletion of protein tyrosine phosphatase SHP-1 restores SUMOylation of podocin and reverses the progression of diabetic kidney disease. Kidney Int 2023; 104:787-802. [PMID: 37507049 DOI: 10.1016/j.kint.2023.06.038] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 06/03/2023] [Accepted: 06/29/2023] [Indexed: 07/30/2023]
Abstract
Both clinical and experimental data suggest that podocyte injury is involved in the onset and progression of diabetic kidney disease (DKD). Although the mechanisms underlying the development of podocyte loss are not completely understood, critical structural proteins such as podocin play a major role in podocyte survival and function. We have reported that the protein tyrosine phosphatase SHP-1 expression increased in podocytes of diabetic mice and glomeruli of patients with diabetes. However, the in vivo contribution of SHP-1 in podocytes is unknown. Conditional podocyte-specific SHP-1-deficient mice (Podo-SHP-1-/-) were generated to evaluate the impact of SHP-1 deletion at four weeks of age (early) prior to the onset of diabetes and after 20 weeks (late) of diabetes (DM; Ins2+/C96Y) on kidney function (albuminuria and glomerular filtration rate) and kidney pathology. Ablation of the SHP-1 gene specifically in podocytes prevented and even reversed the elevated albumin/creatinine ratio, glomerular filtration rate progression, mesangial cell expansion, glomerular hypertrophy, glomerular basement membrane thickening and podocyte foot process effacement induced by diabetes. Moreover, podocyte-specific deletion of SHP-1 at an early and late stage prevented diabetes-induced expression of collagen IV, fibronectin, transforming growth factor-β, transforming protein RhoA, and serine/threonine kinase ROCK1, whereas it restored nephrin, podocin and cation channel TRPC6 expression. Mass spectrometry analysis revealed that SHP-1 reduced SUMO2 post-translational modification of podocin while podocyte-specific deletion of SHP-1 preserved slit diaphragm protein complexes in the diabetic context. Thus, our data uncovered a new role of SHP-1 in the regulation of cytoskeleton dynamics and slit diaphragm protein expression/stability, and its inhibition preserved podocyte function preventing DKD progression.
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Affiliation(s)
- Farah Lizotte
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Marina Rousseau
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Benoit Denhez
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Dominique Lévesque
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Andréanne Guay
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - HongBo Liu
- Renal, Electrolyte, and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Genetics Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Julie Moreau
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Sarah Higgins
- Division of Nephrology, Department of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Robert Sabbagh
- Department of Surgery, Université de Sherbrooke, Québec, Canada
| | - Katalin Susztak
- Renal, Electrolyte, and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Genetics Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | | | - Anne Marie Côté
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada; Division of Nephrology, Department of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Pedro Geraldes
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada; Division of Endocrinology, Department of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada.
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Guo Z, Chilufya MM, Deng H, Qiao L, Liu J, Xiao X, Zhao Y, Lin X, Liu H, Xiang R, Han J. Single and Combined Effects of Short-Term Selenium Deficiency and T-2 Toxin-Induced Kidney Pathological Injury Through the MMPs/TIMPs System. Biol Trace Elem Res 2023; 201:4850-4860. [PMID: 36645617 DOI: 10.1007/s12011-023-03566-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 01/11/2023] [Indexed: 01/17/2023]
Abstract
The single and combined effects of short-term selenium (Se) deficiency and T-2 toxin-induced kidney pathological injury through the MMPs/TIMPs system were investigated. Forty-eight rats were randomly divided into control, 10 ng/g T-2 toxin, 100 ng/g T-2 toxin, Se-deficient, 10 ng/g T-2 toxin and Se deficiency combined, and 100 ng/g T-2 toxin and Se deficiency combined groups for a 4-week intervention. The kidney Se concentration was measured to evaluate the construction of animal models of Se deficiency. Kidney tissues were analyzed by hematoxylin-eosin staining, Masson staining, and transmission electron microscope to observe the pathological changes, the severity of kidney fibrosis, and ultrastructural changes, respectively. Meanwhile, quantitative polymerase chain reaction and immunohistochemical staining were used to analyze the gene and protein expression levels of matrix metallopeptidase 2/3 (MMP2/3) and tissue inhibitor of metalloproteinase 1 (TIMP1). The results showed that short-term Se deficiency and T-2 toxin exposure can cause kidney injury through tubular degeneration and even lead to kidney fibrosis. And the combination of T-2 toxin and Se deficiency had a synergistic effect on the kidney. A dose-response effect of the T-2 toxin was also observed. At the gene and protein levels, the expression of MMP2/3 in the intervention group increased, while the expression of TIMP1 decreased compared with the control group. In conclusion, short-term Se deficiency and T-2 toxin exposure might lead to injury and even the development of fibrosis in the kidneys, and combined intervention can increase the severity with a dose-dependent trend. MMP2/3 and TIMP1 likely play a significant role in the development of kidney fibrosis.
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Affiliation(s)
- Ziwei Guo
- Department of Occupational and Environmental Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
- Health Science Center, Global Health Institute, Xi'an Jiaotong University, Xi'an, 712000, China
| | - Mumba Mulutula Chilufya
- Department of Occupational and Environmental Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
- Health Science Center, Global Health Institute, Xi'an Jiaotong University, Xi'an, 712000, China
| | - Huan Deng
- Department of Occupational and Environmental Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
- Health Science Center, Global Health Institute, Xi'an Jiaotong University, Xi'an, 712000, China
| | - Lichun Qiao
- Department of Occupational and Environmental Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
- Health Science Center, Global Health Institute, Xi'an Jiaotong University, Xi'an, 712000, China
| | - Jiaxin Liu
- Department of Occupational and Environmental Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
- Health Science Center, Global Health Institute, Xi'an Jiaotong University, Xi'an, 712000, China
| | - Xiang Xiao
- Department of Occupational and Environmental Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
- Health Science Center, Global Health Institute, Xi'an Jiaotong University, Xi'an, 712000, China
| | - Yan Zhao
- Department of Occupational and Environmental Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
- Health Science Center, Global Health Institute, Xi'an Jiaotong University, Xi'an, 712000, China
| | - Xue Lin
- Department of Occupational and Environmental Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
- Health Science Center, Global Health Institute, Xi'an Jiaotong University, Xi'an, 712000, China
| | - Haobiao Liu
- Department of Occupational and Environmental Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
- Health Science Center, Global Health Institute, Xi'an Jiaotong University, Xi'an, 712000, China
| | - Rongqi Xiang
- Department of Occupational and Environmental Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
- Health Science Center, Global Health Institute, Xi'an Jiaotong University, Xi'an, 712000, China
| | - Jing Han
- Department of Occupational and Environmental Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China.
- Health Science Center, Global Health Institute, Xi'an Jiaotong University, Xi'an, 712000, China.
- Key Laboratory of Environment and Genes Related to Diseases, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China.
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Hejazian SM, Ardalan M, Hosseiniyan Khatibi SM, Rahbar Saadat Y, Barzegari A, Gueguen V, Meddahi-Pellé A, Anagnostou F, Zununi Vahed S, Pavon-Djavid G. Biofactors regulating mitochondrial function and dynamics in podocytes and podocytopathies. J Cell Physiol 2023; 238:2206-2227. [PMID: 37659096 DOI: 10.1002/jcp.31110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/25/2023] [Accepted: 08/14/2023] [Indexed: 09/04/2023]
Abstract
Podocytes are terminally differentiated kidney cells acting as the main gatekeepers of the glomerular filtration barrier; hence, inhibiting proteinuria. Podocytopathies are classified as kidney diseases caused by podocyte damage. Different genetic and environmental risk factors can cause podocyte damage and death. Recent evidence shows that mitochondrial dysfunction also contributes to podocyte damage. Understanding alterations in mitochondrial metabolism and function in podocytopathies and whether altered mitochondrial homeostasis/dynamics is a cause or effect of podocyte damage are issues that need in-depth studies. This review highlights the roles of mitochondria and their bioenergetics in podocytes. Then, factors/signalings that regulate mitochondria in podocytes are discussed. After that, the role of mitochondrial dysfunction is reviewed in podocyte injury and the development of different podocytopathies. Finally, the mitochondrial therapeutic targets are considered.
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Affiliation(s)
| | | | | | | | - Abolfazl Barzegari
- Université Sorbonne Paris Nord, INSERM U1148, Laboratory for Vascular Translational Science, Cardiovascular Bioengineering, Villetaneuse, France
| | - Virginie Gueguen
- Université Sorbonne Paris Nord, INSERM U1148, Laboratory for Vascular Translational Science, Cardiovascular Bioengineering, Villetaneuse, France
| | - Anne Meddahi-Pellé
- Université Sorbonne Paris Nord, INSERM U1148, Laboratory for Vascular Translational Science, Cardiovascular Bioengineering, Villetaneuse, France
| | - Fani Anagnostou
- Université de Paris, CNRS UMR 7052 INSERM U1271, B3OA, Paris, France
| | | | - Graciela Pavon-Djavid
- Université Sorbonne Paris Nord, INSERM U1148, Laboratory for Vascular Translational Science, Cardiovascular Bioengineering, Villetaneuse, France
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Pokharel A, Anderson JD, Deebajah M, Blatt NB, Reddy G, Garlapaty V, Li W, Kanaan HD, Zhang PL. Podocytopathies related to either COVID-19 infection or its vaccination, our experience and literature review. Ultrastruct Pathol 2023; 47:373-381. [PMID: 37463165 DOI: 10.1080/01913123.2023.2237565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/13/2023] [Accepted: 07/13/2023] [Indexed: 07/20/2023]
Abstract
Coronavirus disease 2019 (COVID-19) affects several organs including the kidney resulting in acute kidney injury (AKI) and variants of podocytopathies. From the beginning to the middle period of the COVID-19 pandemic, we have collected eight renal biopsies with various renal diseases including 4 podocytopathies. In addition, from the middle period to the near end of the COVID-19 pandemic, we have seen two of the patients who developed nephrotic syndrome following COVID-19 vaccination. Three of 4 podocytopathies were collapsing glomerulopathy (also called collapsing focal segmental glomerulosclerosis) and the fourth was a minimal change disease (MCD). Two of three collapsing glomerulopathy were found in African American patients, one of who was tested positive for having the high-risk allele APOL-1 G1. In addition, the two renal biopsies showed either MCD or replaced MCD following COVID-19 vaccination. MCD can be a rare complication following COVID-19 infection and COVID-19 vaccination, raising the question if there are similar antigens induced by the infection or by the vaccination that trigger the MCD. This article reports our experience of diagnosing podocytopathies related to either COVID-19 infection or its vaccination and provides a literature review regarding the incidence and potential pathophysiology in the field.
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Affiliation(s)
- Ashbita Pokharel
- Department of Pathology, Corewell Health (East), Royal Oak, MI, USA
| | | | - Mustafa Deebajah
- Department of Pathology, Corewell Health (East), Royal Oak, MI, USA
| | - Neal B Blatt
- Division of Pediatric Nephrology, Corewell Health (East), Royal Oak, MI, USA
| | - Gampala Reddy
- Division of Nephrology, Corewell Health (East), Royal Oak, MI, USA
| | - Vamshi Garlapaty
- Division of Nephrology, Corewell Health (East), Royal Oak, MI, USA
| | - Wei Li
- Department of Pathology, Corewell Health (East), Royal Oak, MI, USA
| | - Hassan D Kanaan
- Department of Pathology, Corewell Health (East), Royal Oak, MI, USA
| | - Ping L Zhang
- Department of Pathology, Corewell Health (East), Royal Oak, MI, USA
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Al Riyami MS, Al Alawi I, Al Gaithi B, Al Maskari A, Al Kalbani N, Al Hashmi N, Al Balushi A, Al Shahi M, Al Saidi S, Al Bimani M, Al Hatali F, Mabillard H, Sayer JA. Genetic analysis and outcomes of Omani children with steroid-resistant nephrotic syndrome. Mol Genet Genomic Med 2023; 11:e2201. [PMID: 37204080 PMCID: PMC10496054 DOI: 10.1002/mgg3.2201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 04/28/2023] [Accepted: 05/04/2023] [Indexed: 05/20/2023] Open
Abstract
BACKGROUND Nephrotic syndrome (NS) is one of the most common kidney disorders seen by pediatric nephrologists and is defined by the presence of heavy proteinuria (>3.5 g/24 h), hypoalbuminemia (<3.5 g/dL), edema, and hyperlipidemia. Most children with NS are steroid-responsive and have a good prognosis following treatment with prednisolone. However, 10%-20% of them have steroid-resistant nephrotic syndrome (SRNS) and fail to respond to treatment. A significant proportion of these children progress to kidney failure. METHODS This retrospective study aimed to determine the underlying genetic causes of SRNS among Omani children below 13 years old, over a 15-year period and included 77 children from 50 different families. We used targeted Sanger sequencing combined with next-generation sequencing approaches to perform molecular diagnostics. RESULTS We found a high rate of underlying genetic causes of SRNS in 61 (79.2%) children with pathogenic variants in the associated genes. Most of these genetically solved SRNS patients were born to consanguineous parents and variants were in the homozygous state. Pathogenic variants in NPHS2 were the most common cause of SRNS in our study seen in 37 (48.05%) cases. Pathogenic variants in NPHS1 were also seen in 16 cases, especially in infants with congenital nephrotic syndrome (CNS). Other genetic causes identified included pathogenic variants in LAMB2, PLCE1, MYO1E, and NUP93. CONCLUSION NPHS2 and NPHS1 genetic variants were the most common inherited causes of SRNS in Omani children. However, patients with variants in several other SRNS causative genes were also identified. We recommend screening for all genes responsible for SRNS in all children who present with this phenotype, which will assist in clinical management decisions and genetic counseling for the affected families.
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Affiliation(s)
| | - Intisar Al Alawi
- Translational and Clinical Research Institute, Faculty of Medical ScienceNewcastle UniversityNewcastle upon TyneUK
- National Genetic Center, Ministry of HealthMuscatOman
| | - Badria Al Gaithi
- Pediatric Nephrology Unit, Department of Child HealthyRoyal HospitalMuscatOman
| | - Anisa Al Maskari
- Pediatric Nephrology Unit, Department of Child HealthyRoyal HospitalMuscatOman
| | - Naifain Al Kalbani
- Pediatric Nephrology Unit, Department of Child HealthyRoyal HospitalMuscatOman
| | - Nadia Al Hashmi
- Pediatric Metabolic and Genetic Disorder UnitRoyal HospitalMuscatOman
| | - Aisha Al Balushi
- Pediatric Metabolic and Genetic Disorder UnitRoyal HospitalMuscatOman
| | - Maryam Al Shahi
- Pediatric Clinical Genetic Unit, Royal Hospital, Department of Child HealthRoyal HospitalMuscatOman
| | - Suliman Al Saidi
- Pediatric Nephrology Unit, Department of Child HealthyRoyal HospitalMuscatOman
| | | | | | - Holly Mabillard
- Translational and Clinical Research Institute, Faculty of Medical ScienceNewcastle UniversityNewcastle upon TyneUK
- Renal ServicesThe Newcastle upon Tyne Hospitals NHS Foundation TrustNewcastle upon TyneUK
- Newcastle Biomedical Research Center, NIHRNewcastle upon TyneUK
| | - John A. Sayer
- Translational and Clinical Research Institute, Faculty of Medical ScienceNewcastle UniversityNewcastle upon TyneUK
- Renal ServicesThe Newcastle upon Tyne Hospitals NHS Foundation TrustNewcastle upon TyneUK
- Newcastle Biomedical Research Center, NIHRNewcastle upon TyneUK
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Williams AE, Esezobor CI, Lane BM, Gbadegesin RA. Hiding in plain sight: genetics of childhood steroid-resistant nephrotic syndrome in Sub-Saharan Africa. Pediatr Nephrol 2023; 38:2003-2012. [PMID: 36459247 PMCID: PMC10416081 DOI: 10.1007/s00467-022-05831-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 11/14/2022] [Accepted: 11/14/2022] [Indexed: 12/03/2022]
Abstract
Steroid-resistant nephrotic syndrome (SRNS) is the most severe form of childhood nephrotic syndrome with an increased risk of progression to chronic kidney disease stage 5. Research endeavors to date have identified more than 80 genes that are associated with SRNS. Most of these genes regulate the structure and function of the podocyte, the visceral epithelial cells of the glomerulus. Although individuals of African ancestry have the highest prevalence of SRNS, especially those from Sub-Saharan Africa (SSA), with rates as high as 30-40% of all cases of nephrotic syndrome, studies focusing on the characterization and understanding of the genetic basis of SRNS in the region are negligible compared with Europe and North America. Therefore, it remains unclear if some of the variants in SRNS genes that are deemed pathogenic for SRNS are truly disease causing, and if the leading causes of monogenic nephrotic syndrome in other populations are the same for children in SSA with SRNS. Other implications of this lack of genetic data for SRNS in the region include the exclusion of children from the region from clinical trials aimed at identifying potential novel therapeutic agents for this severe form of nephrotic syndrome. This review underlines a need for concerted efforts to advance the genetic basis of SRNS in children in SSA. Such endeavors will complement global efforts at understanding the genetic basis of nephrotic syndrome.
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Affiliation(s)
- Anna Elizabeth Williams
- Department of Pediatrics, Division of Nephrology, Duke University Medical Center, Durham, NC, 27710, USA
| | - Christopher I Esezobor
- Department of Pediatrics, Faculty of Clinical Sciences, College of Medicine, University of Lagos, Lagos, Nigeria
| | - Brandon M Lane
- Department of Pediatrics, Division of Nephrology, Duke University Medical Center, Durham, NC, 27710, USA
- Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
| | - Rasheed A Gbadegesin
- Department of Pediatrics, Division of Nephrology, Duke University Medical Center, Durham, NC, 27710, USA.
- Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
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Vöing K, Michgehl U, Mertens ND, Picciotto C, Maywald ML, Goretzko J, Waimann S, Gilhaus K, Rogg M, Schell C, Klingauf J, Tsytsyura Y, Hansen U, van Marck V, Edinger AL, Vollenbröker B, Rescher U, Braun DA, George B, Weide T, Pavenstädt H. Disruption of the Rab7-Dependent Final Common Pathway of Endosomal and Autophagic Processing Results in a Severe Podocytopathy. J Am Soc Nephrol 2023; 34:1191-1206. [PMID: 37022133 PMCID: PMC10356157 DOI: 10.1681/asn.0000000000000126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 03/03/2023] [Indexed: 04/07/2023] Open
Abstract
SIGNIFICANCE STATEMENT Endocytosis, recycling, and degradation of proteins are essential functions of mammalian cells, especially for terminally differentiated cells with limited regeneration rates and complex morphology, such as podocytes. To improve our understanding on how disturbances of these trafficking pathways are linked to podocyte depletion and slit diaphragm (SD) injury, the authors explored the role of the small GTPase Rab7, which is linked to endosomal, lysosomal, and autophagic pathways, using as model systems mice and Drosophila with podocyte-specific or nephrocyte-specific loss of Rab7, and a human podocyte cell line depleted for Rab7. Their findings point to maturation and fusion events during endolysosomal and autophagic maturation as key processes for podocyte homeostasis and function and identify altered lysosomal pH values as a putative novel mechanism for podocytopathies. BACKGROUND Endocytosis, recycling, and degradation of proteins are essential functions of mammalian cells, especially for terminally differentiated cells with limited regeneration rates, such as podocytes. How disturbances within these trafficking pathways may act as factors in proteinuric glomerular diseases is poorly understood. METHODS To explore how disturbances in trafficking pathways may act as factors in proteinuric glomerular diseases, we focused on Rab7, a highly conserved GTPase that controls the homeostasis of late endolysosomal and autophagic processes. We generated mouse and Drosophila in vivo models lacking Rab7 exclusively in podocytes or nephrocytes, and performed histologic and ultrastructural analyses. To further investigate Rab7 function on lysosomal and autophagic structures, we used immortalized human cell lines depleted for Rab7. RESULTS Depletion of Rab7 in mice, Drosophila , and immortalized human cell lines resulted in an accumulation of diverse vesicular structures resembling multivesicular bodies, autophagosomes, and autoendolysosomes. Mice lacking Rab7 developed a severe and lethal renal phenotype with early-onset proteinuria and global or focal segmental glomerulosclerosis, accompanied by an altered distribution of slit diaphragm proteins. Remarkably, structures resembling multivesicular bodies began forming within 2 weeks after birth, prior to the glomerular injuries. In Drosophila nephrocytes, Rab7 knockdown resulted in the accumulation of vesicles and reduced slit diaphragms. In vitro , Rab7 knockout led to similar enlarged vesicles and altered lysosomal pH values, accompanied by an accumulation of lysosomal marker proteins. CONCLUSIONS Disruption within the final common pathway of endocytic and autophagic processes may be a novel and insufficiently understood mechanism regulating podocyte health and disease.
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Affiliation(s)
- Kristin Vöing
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
| | - Ulf Michgehl
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
| | - Nils David Mertens
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
| | - Cara Picciotto
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
| | - Mee-Ling Maywald
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
| | - Jonas Goretzko
- Research Group Regulatory Mechanisms of Inflammation, Institute of Medical Biochemistry, Centre for Molecular Biology of Inflammation, University of Muenster, Muenster, Germany
| | - Sofie Waimann
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
| | - Kevin Gilhaus
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
| | - Manuel Rogg
- Institute of Surgical Pathology, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany
- Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany
| | - Christoph Schell
- Institute of Surgical Pathology, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany
- Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany
| | - Jürgen Klingauf
- Institute of Medical Physics and Biophysics, University of Muenster, Muenster, Germany
| | - Yaroslav Tsytsyura
- Institute of Medical Physics and Biophysics, University of Muenster, Muenster, Germany
| | - Uwe Hansen
- Institute for Musculoskeletal Medicine (IMM), University of Muenster, Muenster, Germany
| | - Veerle van Marck
- Department of Pathology, University Hospital Muenster Muenster, Germany
| | - Aimee L. Edinger
- Department of Developmental & Cell Biology, University of California, Irvine, California
| | - Beate Vollenbröker
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
| | - Ursula Rescher
- Research Group Regulatory Mechanisms of Inflammation, Institute of Medical Biochemistry, Centre for Molecular Biology of Inflammation, University of Muenster, Muenster, Germany
| | - Daniela Anne Braun
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
| | - Britta George
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
| | - Thomas Weide
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
| | - Hermann Pavenstädt
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
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Marcos González S, Rodrigo Calabia E, Varela I, Červienka M, Freire Salinas J, Gómez Román JJ. High Rate of Mutations of Adhesion Molecules and Extracellular Matrix Glycoproteins in Patients with Adult-Onset Focal and Segmental Glomerulosclerosis. Biomedicines 2023; 11:1764. [PMID: 37371859 DOI: 10.3390/biomedicines11061764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/15/2023] [Accepted: 06/18/2023] [Indexed: 06/29/2023] Open
Abstract
(1) Background: Focal and segmental glomerulosclerosis (FSGS) is a pattern of injury that results from podocyte loss in the setting of a wide variety of injurious mechanisms. These include both acquired and genetic as well as primary and secondary causes, or a combination thereof, without optimal therapy, and a high rate of patients develop end-stage renal disease (ESRD). Genetic studies have helped improve the global understanding of FSGS syndrome; thus, we hypothesize that patients with primary FSGS may have underlying alterations in adhesion molecules or extracellular matrix glycoproteins related to previously unreported mutations that may be studied through next-generation sequencing (NGS). (2) Methods: We developed an NGS panel with 29 genes related to adhesion and extracellular matrix glycoproteins. DNA was extracted from twenty-three FSGS patients diagnosed by renal biopsy; (3) Results: The average number of accumulated variants in FSGS patients was high. We describe the missense variant ITGB3c.1199G>A, which is considered pathogenic; in addition, we discovered the nonsense variant CDH1c.499G>T, which lacks a Reference SNP (rs) Report and is considered likely pathogenic. (4) Conclusions: To the best of our knowledge, this is the first account of a high rate of change in extracellular matrix glycoproteins and adhesion molecules in individuals with adult-onset FSGS. The combined effect of all these variations may result in a genotype that is vulnerable to the pathogenesis of glomerulopathy.
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Affiliation(s)
- Sara Marcos González
- Pathology Department, Marqués de Valdecilla University Hospital, Institute of Research Valdecilla (IDIVAL), 39008 Santander, Spain
| | - Emilio Rodrigo Calabia
- Nephrology Department, Marqués de Valdecilla University Hospital, 39008, University of Cantabria, 39005 Santander, Spain
| | - Ignacio Varela
- Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), 39011, University of Cantabria-CSIC, 39005 Santander, Spain
| | - Michal Červienka
- Nephrology Department, Rio Carrion General Hospital, 34005 Palencia, Spain
| | - Javier Freire Salinas
- Anatomic Pathology, Marqués de Valdecilla University Hospital, Institute of Research Valdecilla (IDIVAL), 39008 Santander, Spain
| | - José Javier Gómez Román
- Pathology Department, Marqués de Valdecilla University Hospital, Institute of Research Valdecilla (IDIVAL), School of Medicine, University of Cantabria, 39008 Santander, Spain
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Maggiore JC, LeGraw R, Przepiorski A, Velazquez J, Chaney C, Streeter E, Silva-Barbosa A, Franks J, Hislop J, Hill A, Wu H, Pfister K, Howden SE, Watkins SC, Little M, Humphreys BD, Watson A, Stolz DB, Kiani S, Davidson AJ, Carroll TJ, Cleaver O, Sims-Lucas S, Ebrahimkhani MR, Hukriede NA. Genetically engineering endothelial niche in human kidney organoids enables multilineage maturation, vascularization and de novo cell types. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.30.542848. [PMID: 37333155 PMCID: PMC10274893 DOI: 10.1101/2023.05.30.542848] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/20/2023]
Abstract
Vascularization plays a critical role in organ maturation and cell type development. Drug discovery, organ mimicry, and ultimately transplantation in a clinical setting thereby hinges on achieving robust vascularization of in vitro engineered organs. Here, focusing on human kidney organoids, we overcome this hurdle by combining an inducible ETS translocation variant 2 (ETV2) human induced pluripotent stem cell (iPSC) line, which directs endothelial fate, with a non-transgenic iPSC line in suspension organoid culture. The resulting human kidney organoids show extensive vascularization by endothelial cells with an identity most closely related to endogenous kidney endothelia. Vascularized organoids also show increased maturation of nephron structures including more mature podocytes with improved marker expression, foot process interdigitation, an associated fenestrated endothelium, and the presence of renin+ cells. The creation of an engineered vascular niche capable of improving kidney organoid maturation and cell type complexity is a significant step forward in the path to clinical translation. Furthermore, this approach is orthogonal to native tissue differentiation paths, hence readily adaptable to other organoid systems and thus has the potential for a broad impact on basic and translational organoid studies.
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Affiliation(s)
- Joseph C Maggiore
- Department of Developmental Biology, School of Medicine, University of Pittsburgh, Pittsburgh PA 15213, USA
| | - Ryan LeGraw
- Department of Pathology, Division of Experimental Pathology, School of Medicine, University of Pittsburgh, Pittsburgh PA 15213, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Aneta Przepiorski
- Department of Developmental Biology, School of Medicine, University of Pittsburgh, Pittsburgh PA 15213, USA
| | - Jeremy Velazquez
- Department of Pathology, Division of Experimental Pathology, School of Medicine, University of Pittsburgh, Pittsburgh PA 15213, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Christopher Chaney
- Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Evan Streeter
- Department of Developmental Biology, School of Medicine, University of Pittsburgh, Pittsburgh PA 15213, USA
| | - Anne Silva-Barbosa
- Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh PA, 15213
| | - Jonathan Franks
- Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Joshua Hislop
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Alex Hill
- Department of Pathology, Division of Experimental Pathology, School of Medicine, University of Pittsburgh, Pittsburgh PA 15213, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Haojia Wu
- Division of Nephrology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, MO 63130
| | - Katherine Pfister
- Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh PA, 15213
| | - Sara E Howden
- Murdoch Children's Research Institute, Melbourne, Victoria, Australia
| | - Simon C Watkins
- Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Melissa Little
- Murdoch Children's Research Institute, Melbourne, Victoria, Australia
- Department of Anatomy and Neuroscience, The University of Melbourne, Melbourne, Victoria, Australia
- Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia
| | - Benjamin D Humphreys
- Division of Nephrology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, MO 63130
- Department of Developmental Biology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63130
| | - Alan Watson
- Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Donna B Stolz
- Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Samira Kiani
- Department of Pathology, Division of Experimental Pathology, School of Medicine, University of Pittsburgh, Pittsburgh PA 15213, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Alan J Davidson
- Department of Molecular Medicine and Pathology, University of Auckland, Auckland 1010, New Zealand
| | - Thomas J Carroll
- Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Ondine Cleaver
- Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390
| | - Sunder Sims-Lucas
- Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh PA, 15213
| | - Mo R Ebrahimkhani
- Department of Pathology, Division of Experimental Pathology, School of Medicine, University of Pittsburgh, Pittsburgh PA 15213, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Neil A Hukriede
- Department of Developmental Biology, School of Medicine, University of Pittsburgh, Pittsburgh PA 15213, USA
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Al-Azzawy MF, Al-Haggar M, ElSaid AM, El-Khawaga OY. Analysis of the association of NPHS2 and ACTN4 genes polymorphism with nephrotic syndrome in Egyptian children. Mol Biol Rep 2023; 50:4481-4490. [PMID: 37014572 PMCID: PMC10147774 DOI: 10.1007/s11033-023-08387-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 03/14/2023] [Indexed: 04/05/2023]
Abstract
BACKGROUND One of the most common kidney illnesses in developing countries is pediatric nephrotic syndrome (PNS), which is frequently associated with dyslipidemia and edema. The rapid discovery of genes related to NS has aided in the understanding of the molecular mechanics of glomerular filtration. The goal of this study is to determine the relationship between NPHS2 and ACTN4 in PNS youngsters. METHODS A study with 100 NS children and 100 healthy matched volunteers was conducted. Genomic DNA was extracted from peripheral blood. Single-nucleotide polymorphisms were genotyped using ARMS-PCR. RESULTS A substantial decline in the level of albumin was found in NS cases (P < 0.001) Further on, a significantly difference in T.C and TG level between healthy and NS patient. Molecular study showed a highly significant difference of NS patients from controls regarding NPHS2 rs3829795 polymorphic genotypes as the GA heterozygous genotype shows highly significant difference from controls (P < 0.001) as well as GA + AA genotypes (P < 0.001) in comparison with GG genotype. Regarding rs2274625, The GA heterozygous genotype showed no statistically significant difference between genotypes and alleles with NS (P = 0.246). Association of AG haplotype NPHS2 rs3829795-rs2274625 haplotypes found a significant association with the risk of developing NS (P = 0.008). Concerning the ACTN4 rs121908415 SNP, there was no link between this mutation and NS children. CONCLUSION The correlation of AG haplotype NPHS2 rs3829795-rs2274625 haplotypes identified a strong association with the likelihood of getting NS, according to our findings. There was no connection found between the ACTN4 rs121908415 SNP and NS children.
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Affiliation(s)
- Mohammed F Al-Azzawy
- Biochemistry Division, Chemistry Department, Faculty of Science, Mansoura University, Mansoura, 35516, Egypt
| | - Mohammad Al-Haggar
- Genetic Unit, Department of Pediatrics, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt
| | - Afaf M ElSaid
- Genetic Unit, Department of Pediatrics, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt
| | - Omali Y El-Khawaga
- Biochemistry Division, Chemistry Department, Faculty of Science, Mansoura University, Mansoura, 35516, Egypt.
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