|
1
|
Elliott J, Tang PK. Fibroblast growth factor 23 - A review with particular reference to the physiology and pathophysiology of phosphate homeostasis in the cat. Vet J 2025; 309:106271. [PMID: 39608700 DOI: 10.1016/j.tvjl.2024.106271] [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: 07/04/2024] [Revised: 09/08/2024] [Accepted: 11/24/2024] [Indexed: 11/30/2024]
Abstract
Fibroblast growth factor-23 (FGF23) is a phosphaturic hormone, discovery of which has transformed our understanding of mineral regulation in healthy mammals, including the cat. It is produced by osteoblasts and osteocytes and its prime role is to regulate phosphate entry into extracellular fluid (from bone and via the gut) and its excretion via the kidney. It interacts with other hormones (calcitriol and parathyroid hormone), inhibiting their activation and secretion respectively and so impacts on calcium as well as phosphate homeostasis. Physiological factors regulating its secretion are not well understood, although phosphate ion sensing is likely to be important. Calcium and magnesium ions are also involved and unravelling the control points and integration of the system regulating bone turnover and mineral balance whilst preventing soft tissue (non-osseous) mineralisation is a future research goal. Calciprotein particle size and number likely play an important role in this system but precisely how remains to be determined. Elevated serum FGF23 is the earliest indicator of mineral bone disorder associated with chronic kidney disease in human patients and in cats, enabling reference-range serum phosphorus to be maintained despite reduction in glomerular filtration rate which limits phosphate excretion. FGF23 also predicts CKD progression and survival in cats. The many factors influencing its secretion at different stages of CKD, including relative iron deficiency, anaemia and chronic systemic inflammation, hypomagnesaemia and α-klotho deficiency are discussed in this review, where the data available in cats with naturally occurring CKD is presented alongside that from rodent models and human CKD patients.
Collapse
Affiliation(s)
- Jonathan Elliott
- Department of Comparative Biomedical Sciences, Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, United Kingdom.
| | - Pak Kan Tang
- Department of Comparative Biomedical Sciences, Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, United Kingdom
| |
Collapse
|
|
2
|
Xu P, Jiang M, Chen J, Zhou Y, Wang Z. The Long-Range Chromosomal Interaction Controlling Klotho Gene Expression in Human Chronic Kidney Disease. ACS OMEGA 2024; 9:51264-51270. [PMID: 39758635 PMCID: PMC11696417 DOI: 10.1021/acsomega.4c07967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 11/22/2024] [Accepted: 12/02/2024] [Indexed: 01/07/2025]
Abstract
Cis-regulatory elements bridge enhancers and gene promoters to control gene expression via distal DNA interaction and three-dimensional chromosomal conformation organization. The aberrant changes of cis-acting regulatory systems as one type of the epigenetic regulative ways may be connected with human genetic diseases. Klotho, as an antiaging protein, is selectively expressed in kidney tissues and plays a crucial role in preventing chronic kidney disease (CKD) and renal fibrosis. However, the underlying transcription regulatory mechanism of Klotho in CKD is not fully understood. Herein, we analyzed the spatial organization of the chromatin region spanning 2 Mb upstream Klotho in human renal punctured CKD tissues using chromosome conformation capture (3C)-qPCR and identified the distal interaction of the Klotho promoter with certain specific chromatin regions characterized as the regulatory elements. Moreover, we determined that four DNase I hypersensitive sites (DHSs) involved in the regulation of Klotho gene expression lost their activities in CKD tissues compared to control accompanied by the reduction of H3K27ac. Finally, the CCCTC-binding factor (CTCF) sites were validated on the DHSs beyond the Klotho promoter by chromatin looping formation through the recruitment of CTCF.
Collapse
Affiliation(s)
- Pengwei Xu
- Department of Urology, Suzhou Ninth Hospital affiliated to Soochow University, Suzhou 215000, China
| | - Minjun Jiang
- Department of Urology, Suzhou Ninth Hospital affiliated to Soochow University, Suzhou 215000, China
| | - Jianchun Chen
- Department of Urology, Suzhou Ninth Hospital affiliated to Soochow University, Suzhou 215000, China
| | - Yongqiang Zhou
- Department of Urology, Suzhou Ninth Hospital affiliated to Soochow University, Suzhou 215000, China
| | - Zhenfan Wang
- Department of Urology, Suzhou Ninth Hospital affiliated to Soochow University, Suzhou 215000, China
| |
Collapse
|
|
3
|
Tang J, Xu Z, Ren L, Xu J, Chen X, Jin Y, Liang R, Zhang H. Association of serum Klotho with the severity and mortality among adults with cardiovascular-kidney-metabolic syndrome. Lipids Health Dis 2024; 23:408. [PMID: 39695774 DOI: 10.1186/s12944-024-02400-w] [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: 10/25/2024] [Accepted: 12/06/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Cardiovascular-kidney-metabolic (CKM) syndrome is characterized as a systemic disease resulting from the pathophysiological interplay among metabolic risk factors, chronic kidney disease (CKD), and cardiovascular disease (CVD). The Klotho protein may serve as a novel biomarker. However, the utility of serum Klotho levels as an indicator of severity and mortality risk in CKM syndrome remains uncertain. METHODS This study involved 9,871 participants from the National Health and Nutrition Examination Survey (NHANES) conducted between 2007 and 2016. Serum Klotho levels were measured using an enzyme-linked immunosorbent assay kit. The optimal cutoff value was established through the maximum Youden's index. Multivariable weighted regression models were employed to calculate the odds ratio and hazard ratio, along with the 95% confidence interval, to evaluate the association between serum Klotho levels and the severity of CKM syndrome, as well as all-cause and cardiovascular mortality. Additionally, the receiver operating characteristic curve and restricted cubic spline curves were utilized to assess predictive efficacy and to explore nonlinear relationships. RESULTS After adjusting for potential confounding factors, a non-linear relationship was seen between the Klotho protein, and CKM syndrome. In the multivariable, piecewise logistic regression, when the Serum klotho was less than 801, the risk of CKM syndrome decreased with the increase in Serum klotho (OR = 0.82, 95%CI 0.70, 0.96; p < 0.001). Furthermore, we observed the association when the Serum klotho was greater than 801 (OR = 0.94, 95%CI 0.89, 0.99; p = 0.035). The relationship between serum Klotho levels and all-cause mortality was U-shaped, while the relationship with cardiovascular mortality was L-shaped. Specifically, low serum Klotho levels were associated with an increase in all-cause mortality by 21% and cardiovascular mortality by 76% among patients with CKM syndrome. Furthermore, serum Klotho levels demonstrated excellent predictive efficacy for both the severity and mortality associated with CKM syndrome. CONCLUSIONS This study indicates that low serum Klotho levels serve as reliable indicators of both the severity of CKM syndrome and the associated risk of mortality.
Collapse
Affiliation(s)
- Jiao Tang
- Department of Cardiovascular Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Zhehao Xu
- Department of General Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Li Ren
- Department of Cardiovascular Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Jiahua Xu
- Department of Cardiovascular Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Xin Chen
- Department of Cardiovascular Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Yian Jin
- Department of General Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ruiyun Liang
- Department of Respiratory Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Huanji Zhang
- Department of Cardiovascular Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.
| |
Collapse
|
|
4
|
Wang S, Xu Q, Zhang Y, Jiang X, Wang N, Hu Y, Lu Y, Wang Y, Shao F, Cao H. The FGF23-Klotho axis promotes microinflammation in chronic kidney disease. Cytokine 2024; 184:156781. [PMID: 39454251 DOI: 10.1016/j.cyto.2024.156781] [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: 08/08/2024] [Revised: 09/28/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024]
Abstract
The management of chronic kidney disease (CKD) is a global health challenge. Elevated levels of inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), are associated with higher mortality rates in patients with CKD. Moreover, increased fibroblast growth factor 23 (FGF23) levels are a strong predictor of adverse clinical outcomes in CKD. The production of Klotho, which plays a protective role is decreased in patients with CKD. However, the relationship between FGF23-Klotho and levels of inflammatory factors in patients with CKD is unclear. This study aimed to explore the effects of changes in the FGF23-Klotho axis on inflammatory factors in patients with CKD, with a view to providing ideas for novel treatments of CKD. Clinical data were collected from 85 patients with CKD and 17 healthy subjects admitted to the Department of Nephrology of Henan Provincial People's Hospital between June-August 2023. The differences in biochemical indicators at various stages of CKD and healthy people were analyzed. Using enzyme-linked immunosorbent assay and immunohistochemistry, changes in the FGF23-Klotho axis, and their relationship with interleukin 6 (IL-6) and TNF-α were assessed. FGF23 levels gradually increased from CKD stages 1 to 5, with significant differences observed between stages 3 to 5. Klotho levels significantly decreased in CKD stages 3-5. The levels of C-reactive protein (CRP), IL-6, and TNF-α gradually increased. Overall, FGF23 expression was negatively correlated with Klotho levels and positively correlated with CRP, IL-6, and TNF-α levels. In renal tubular epithelial cells, knockdown of Klotho and overexpression of FGF23 increased the expression of inflammatory factors; however, their levels were significantly lower than that of the Klotho knockdown group. Collectively, these findings demonstrate that in CKD, the FGF23-Klotho axis promotes the expression of inflammatory cytokines in renal tubular epithelial cells.
Collapse
Affiliation(s)
- Shasha Wang
- Graduate School, Xinxiang Medical University, Xinxiang 453000, China; Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People's Hospital, Zhengzhou 450003, China.
| | - Qin Xu
- Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People's Hospital, Zhengzhou 450003, China.
| | - Yue Zhang
- Graduate School, Xinxiang Medical University, Xinxiang 453000, China; Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People's Hospital, Zhengzhou 450003, China.
| | - Xin Jiang
- Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People's Hospital, Zhengzhou 450003, China.
| | - Ning Wang
- Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People's Hospital, Zhengzhou 450003, China.
| | - Yifeng Hu
- Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People's Hospital, Zhengzhou 450003, China.
| | - Yanfang Lu
- Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People's Hospital, Zhengzhou 450003, China.
| | - Yanliang Wang
- Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People's Hospital, Zhengzhou 450003, China.
| | - Fengmin Shao
- Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People's Hospital, Zhengzhou 450003, China.
| | - Huixia Cao
- Graduate School, Xinxiang Medical University, Xinxiang 453000, China; Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People's Hospital, Zhengzhou 450003, China.
| |
Collapse
|
|
5
|
Marando M, Tamburello A, Salera D, Di Lullo L, Bellasi A. Phosphorous metabolism and manipulation in chronic kidney disease. Nephrology (Carlton) 2024; 29:791-800. [PMID: 39433296 PMCID: PMC11579558 DOI: 10.1111/nep.14407] [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: 06/05/2024] [Revised: 09/13/2024] [Accepted: 10/05/2024] [Indexed: 10/23/2024]
Abstract
Chronic kidney disease-mineral bone disorder (CKD-MBD) is a syndrome commonly observed in subjects with impaired renal function. Phosphate metabolism has been implicated in the pathogenesis of CKD-MBD and according to the phosphorocentric hypothesis may be the key player in the pathogenesis of these abnormalities. As phosphorous is an essential component for life, absorption from the bowel, accumulation and release from the bones, and elimination through the kidneys are all homeostatic mechanisms that maintain phosphate balance through very sophisticated feedback mechanisms, which comprise as main actors: vitamin D (VD), parathyroid hormone (PTH), calciproteins particles (CPPs), fibroblast growth factor-23 (FGF-23) and other phosphatonins and klotho. Indeed, as the renal function declines, factors such as FGF-23 and PTH prevent phosphate accumulation and hyperphosphatemia. However, these factors per se may be responsible for the organ damages associated with CKD-MBD, such as bone osteodystrophy and vascular calcification. We herein review the current understanding of the CKD-MBD focusing on phosphorous metabolism and the impact of phosphate manipulation on surrogate and hard outcomes.
Collapse
Affiliation(s)
- Marco Marando
- Service of PneumologyHôpitaux Universitaires de GenèveGenevaSwitzerland
| | | | - Davide Salera
- Department of Internal MedicineOspedale Regionale di Lugano, Ospedale Civico, Ente Ospedaliero CantonaleLuganoSwitzerland
| | - Luca Di Lullo
- UOC Nephrology and Dialysis UnitAzienda USL Roma 6Albano LazialeItaly
| | - Antonio Bellasi
- Service of NephrologyOspedale Regionale di Lugano, Ospedale Civico, Ente Ospedaliero CantonaleLuganoSwitzerland
- Faculty of Biomedical SciencesUniversità della Svizzera italianaLuganoSwitzerland
| |
Collapse
|
|
6
|
Grigore TV, Zuidscherwoude M, Olauson H, Hoenderop JG. Lessons from Klotho mouse models to understand mineral homeostasis. Acta Physiol (Oxf) 2024; 240:e14220. [PMID: 39176993 DOI: 10.1111/apha.14220] [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: 05/31/2024] [Revised: 07/30/2024] [Accepted: 08/14/2024] [Indexed: 08/24/2024]
Abstract
AIM Klotho, a key component of the endocrine fibroblast growth factor receptor-fibroblast growth factor axis, is a multi-functional protein that impacts renal electrolyte handling. The physiological significance of Klotho will be highlighted in the regulation of calcium, phosphate, and potassium metabolism. METHODS In this review, we compare several murine models with different renal targeted deletions of Klotho and the insights into the molecular and physiological function that these models offer. RESULTS In vivo, Klotho deficiency is associated with severely impaired mineral metabolism, with consequences on growth, longevity and disease development. Additionally, we explore the perspectives of Klotho in renal pathology and vascular events, as well as potential Klotho treatment options. CONCLUSION This comprehensive review emphasizes the use of Klotho to shed light on deciphering the renal molecular in vivo mechanisms in electrolyte handling, as well as novel therapeutic interventions.
Collapse
Affiliation(s)
- Teodora V Grigore
- Department of Medical BioSciences, Radboud Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Malou Zuidscherwoude
- Department of Medical BioSciences, Radboud Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Hannes Olauson
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Joost G Hoenderop
- Department of Medical BioSciences, Radboud Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
| |
Collapse
|
|
7
|
Qiu X, Lan X, Li L, Chen H, Zhang N, Zheng X, Xie X. The role of perirenal adipose tissue deposition in chronic kidney disease progression: Mechanisms and therapeutic implications. Life Sci 2024; 352:122866. [PMID: 38936605 DOI: 10.1016/j.lfs.2024.122866] [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: 04/24/2024] [Revised: 06/11/2024] [Accepted: 06/20/2024] [Indexed: 06/29/2024]
Abstract
Chronic kidney disease (CKD) represents a significant and escalating global health challenge, with morbidity and mortality rates rising steadily. Evidence increasingly implicates perirenal adipose tissue (PRAT) deposition as a contributing factor in the pathogenesis of CKD. This review explores how PRAT deposition may exert deleterious effects on renal structure and function. The anatomical proximity of PRAT to the kidneys not only potentially causes mechanical compression but also leads to the dysregulated secretion of adipokines and inflammatory mediators, such as adiponectin, leptin, visfatin, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and exosomes. Additionally, PRAT deposition may contribute to renal lipotoxicity through elevated levels of free fatty acids (FFA), triglycerides (TAG), diacylglycerol (DAG), and ceramides (Cer). PRAT deposition is also linked to the hyperactivation of the renin-angiotensin-aldosterone system (RAAS), which further exacerbates CKD progression. Recognizing PRAT deposition as an independent risk factor for CKD underscores the potential of targeting PRAT as a novel strategy for the prevention and management of CKD. This review further discusses interventions that could include measuring PRAT thickness to establish a baseline, managing metabolic risk factors that promote its deposition, and inhibiting key PRAT-induced signaling pathways.
Collapse
Affiliation(s)
- Xiang Qiu
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, China; Public Center of Experimental Technology, Model Animal and Human Disease Research of Luzhou Key Laboratory, Southwest Medical University, Luzhou, China
| | - Xin Lan
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, China; Public Center of Experimental Technology, Model Animal and Human Disease Research of Luzhou Key Laboratory, Southwest Medical University, Luzhou, China
| | - Langhui Li
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, China; Public Center of Experimental Technology, Model Animal and Human Disease Research of Luzhou Key Laboratory, Southwest Medical University, Luzhou, China
| | - Huan Chen
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, China; Public Center of Experimental Technology, Model Animal and Human Disease Research of Luzhou Key Laboratory, Southwest Medical University, Luzhou, China; Nucleic Acid Medicine of Luzhou Key Laboratory, Southwest Medical University, Luzhou, China
| | - Ningjuan Zhang
- The School of Clinical Medical Sciences, Southwest Medical University, Luzhou, China
| | - Xiaoli Zheng
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, China.
| | - Xiang Xie
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, China; Public Center of Experimental Technology, Model Animal and Human Disease Research of Luzhou Key Laboratory, Southwest Medical University, Luzhou, China.
| |
Collapse
|
|
8
|
Wang F, Colonnello E, Zhang H, Sansone A, Wang C, Dolci S, Guo J, Jannini EA. Comparing Western and traditional Chinese medicine for male sexual dysfunction: can Klotho represent a silk road? Andrology 2024; 12:1215-1223. [PMID: 38155398 DOI: 10.1111/andr.13580] [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: 08/20/2023] [Revised: 10/30/2023] [Accepted: 11/28/2023] [Indexed: 12/30/2023]
Abstract
Traditional Chinese medicine (TCM) and Western Medicine both have shown efficacy in treating male sexual dysfunction (MSD). The aim of this perspective paper is to discuss a possible link between Western medicine and TCM in the MSD field as represented by the entity of Klotho. Klotho is a recently discovered protein, mainly expressed in the kidney, encoded by the anti-aging gene klotho. Not only is Klotho significantly correlated with the development and progression of kidney diseases and their complications, but increasing evidence indicates that it is also closely related to MSD. A comprehensive search within PubMed database was performed to retrieve available evidence on Klotho's roles, particularly in kidney and in MSD. Indeed, in the TCM theory, the concept of the "kidney" is entirely different from the Western medicine: it is closely related to metabolism and to the reproductive, nervous, endocrine systems, being more than just a urinary organ. According to the "Kidney storing essence (jīng) and governing reproduction" (KSEGR) theory, a cornerstone in TCM, the treatment of MSD mainly consists of restoring the kidney's function. Signs of decreasing kidney essence show a consistent similarity to deficiencies of Klotho, also for what regards the male sexual function. Based on the current evidence, Klotho may represent a potential biological indicator for sexual desire and sexual function and a kind of new scientific Silk Road between TCM and Western medicine for MSD; nevertheless, there is a need to conduct further high-quality research to prove this hypothesis.
Collapse
Affiliation(s)
- Fu Wang
- Department of Andrology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Elena Colonnello
- Chair of Endocrinology and Medical Sexology (ENDOSEX), Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Hui Zhang
- Chair of Endocrinology and Medical Sexology (ENDOSEX), Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Andrea Sansone
- Chair of Endocrinology and Medical Sexology (ENDOSEX), Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Chunlin Wang
- Chair of Endocrinology and Medical Sexology (ENDOSEX), Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Susanna Dolci
- Chair of Anatomy, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Jun Guo
- Department of Andrology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Emmanuele A Jannini
- Chair of Endocrinology and Medical Sexology (ENDOSEX), Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| |
Collapse
|
|
9
|
Suzuki K, Soeda K, Komaba H. Crosstalk between kidney and bone: insights from CKD-MBD. J Bone Miner Metab 2024; 42:463-469. [PMID: 39060498 DOI: 10.1007/s00774-024-01528-0] [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: 03/13/2024] [Accepted: 06/17/2024] [Indexed: 07/28/2024]
Abstract
The kidneys play an important role in the regulation of phosphate and calcium balance and serum concentrations, coordinated by fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D (1,25D). In patients with chronic kidney disease (CKD), this regulation is impaired, leading to CKD-mineral and bone disorder (CKD-MBD), characterized by decreased 1,25D, elevated FGF23, secondary hyperparathyroidism, hyperphosphatemia, bone abnormalities, and vascular and soft-tissue calcification. While bone abnormalities associated with CKD-MBD, known as renal osteodystrophy, have been recognized as the most typical interaction between the kidney and bone, a number of other kidney-bone interactions have been identified, for which our knowledge of the pathogenesis of CKD-MBD has played an important role. This article summarizes recent findings on CKD-MBD and explores the crosstalk between the kidney and bone from the perspective of CKD-MBD.
Collapse
Affiliation(s)
- Kodai Suzuki
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, 143 Shimokasuya, Isehara, 259-1193, Japan
- Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Keisuke Soeda
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, 143 Shimokasuya, Isehara, 259-1193, Japan
| | - Hirotaka Komaba
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, 143 Shimokasuya, Isehara, 259-1193, Japan.
- The Institute of Medical Sciences, Tokai University, Isehara, Japan.
| |
Collapse
|
|
10
|
Koike M, Sato T, Shiozaki Y, Komiya A, Miura M, Higashi A, Ishikawa A, Takayanagi K, Uga M, Miyamoto KI, Segawa H. Involvement of α-klotho in growth hormone (GH) signaling. J Clin Biochem Nutr 2024; 74:221-229. [PMID: 38799134 PMCID: PMC11111466 DOI: 10.3164/jcbn.23-127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Accepted: 01/10/2024] [Indexed: 05/29/2024] Open
Abstract
Growth hormone (GH) exerts multiple effects on different organs directly or via its main mediator, insulin-like growth factor1 (IGF1). In this study, we focused on the novel relationship between GH action and the antiaging hormone α-klotho. Immunofluorescent staining of α-klotho was observed in the renal distal tubules and pituitary glands of somatostatin- and GH-positive cells in wild-type (WT) mice. Treatment of 4-week-old WT mice with GH increased IGF1 mRNA expression in the pituitary gland, liver, heart, kidney, and bone but increased α-klotho mRNA expression only in the pituitary gland, kidney, and bone. Increased α-klotho protein levels were observed in the kidney but not in the pituitary gland. No induction of α-klotho RNA expression by GH was observed in juvenile mice with kidney disease, indicating GH resistance. Furthermore, GH and α-klotho supplementation in HEK293 cells transfected with GHR increased Janus kinase 2 mRNA (a GH downstream signal) expression compared to supplementation with GH alone. In conclusion, we suggest that 1) the kidney is the main source of secreted α-klotho, which is detected in blood by the downstream action of GH, 2) α-klotho induction by GH is resistant in kidney disease, and 3) α-klotho might be an enhanced regulator of GH signaling.
Collapse
Affiliation(s)
- Megumi Koike
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Tetsuhiko Sato
- General Medicine, Nagoya Daini Red Cross Hospital, 2-9 Myoken-cho, Showa-ku, Nagoya 466-8650, Japan
| | - Yuji Shiozaki
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Aoi Komiya
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Mizuki Miura
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Ayami Higashi
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Akane Ishikawa
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Kaori Takayanagi
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Minori Uga
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Ken-ichi Miyamoto
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
- Graduate School of Agriculture, Ryukoku University, 1-5 Yokotani, Seta Oe-cho, Otsu, Shiga 520-2194, Japan
| | - Hiroko Segawa
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| |
Collapse
|
|
11
|
Liu J, Wang H, Liu Q, Long S, Wu Y, Wang N, Lin W, Chen G, Lin M, Wen J. Klotho exerts protection in chronic kidney disease associated with regulating inflammatory response and lipid metabolism. Cell Biosci 2024; 14:46. [PMID: 38584258 PMCID: PMC11000353 DOI: 10.1186/s13578-024-01226-4] [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: 10/18/2023] [Accepted: 03/27/2024] [Indexed: 04/09/2024] Open
Abstract
BACKGROUND The anti-aging protein Klotho plays a protective role in kidney disease, but its potential as a biomarker for chronic kidney disease (CKD) is controversial. Additionally, the main pathways through which Klotho exerts its effects on CKD remain unclear. Therefore, we used bioinformatics and clinical data analysis to determine its role in CKD. RESULTS We analyzed the transcriptomic and clinical data from the Nephroseq v5 database and found that the Klotho gene was mainly expressed in the tubulointerstitium, and its expression was significantly positively correlated with estimated glomerular filtration rate (eGFR) and negatively correlated with blood urea nitrogen (BUN) in CKD. We further found that Klotho gene expression was mainly negatively associated with inflammatory response and positively associated with lipid metabolism in CKD tubulointerstitium by analyzing two large sample-size CKD tubulointerstitial transcriptome datasets. By analyzing 10-year clinical data from the National Health and Nutrition Examination Survey (NHANES) 2007-2016, we also found that Klotho negatively correlated with inflammatory biomarkers and triglyceride and positively correlated with eGFR in the CKD population. Mediation analysis showed that Klotho could improve renal function in the general population by modulating the inflammatory response and lipid metabolism, while in the CKD population, it primarily manifested by mediating the inflammatory response. Restricted cubic spline (RCS) analysis showed that the optimal concentration range for Klotho to exert its biological function was around 1000 pg/ml. Kaplan-Meier curves showed that lower cumulative hazards of all-cause mortality in participants with higher levels of Klotho. We also demonstrated that Klotho could reduce cellular inflammatory response and improve cellular lipid metabolism by establishing an in vitro model similar to CKD. CONCLUSIONS Our results suggest that Klotho exerts protection in CKD, which may be mainly related to the regulation of inflammatory response and lipid metabolism, and it can serve as a potential biomarker for CKD.
Collapse
Affiliation(s)
- Junhui Liu
- Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China
- Department of Endocrinology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Huaicheng Wang
- Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China
| | - Qinyu Liu
- Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China
- Department of Endocrinology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Shushu Long
- Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China
- Department of Endocrinology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Yanfang Wu
- Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China
- Department of Endocrinology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Nengying Wang
- Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China
- Department of Endocrinology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Wei Lin
- Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China
- Department of Endocrinology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Gang Chen
- Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China.
- Department of Endocrinology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China.
| | - Miao Lin
- Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China.
- Department of Nephrology, Provincial Clinical College, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China.
| | - Junping Wen
- Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China.
- Department of Endocrinology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China.
| |
Collapse
|
|
12
|
Sisto M, Lisi S. Epigenetic Regulation of EMP/EMT-Dependent Fibrosis. Int J Mol Sci 2024; 25:2775. [PMID: 38474021 PMCID: PMC10931844 DOI: 10.3390/ijms25052775] [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: 12/30/2023] [Revised: 02/23/2024] [Accepted: 02/24/2024] [Indexed: 03/14/2024] Open
Abstract
Fibrosis represents a process characterized by excessive deposition of extracellular matrix (ECM) proteins. It often represents the evolution of pathological conditions, causes organ failure, and can, in extreme cases, compromise the functionality of organs to the point of causing death. In recent years, considerable efforts have been made to understand the molecular mechanisms underlying fibrotic evolution and to identify possible therapeutic strategies. Great interest has been aroused by the discovery of a molecular association between epithelial to mesenchymal plasticity (EMP), in particular epithelial to mesenchymal transition (EMT), and fibrogenesis, which has led to the identification of complex molecular mechanisms closely interconnected with each other, which could explain EMT-dependent fibrosis. However, the result remains unsatisfactory from a therapeutic point of view. In recent years, advances in epigenetics, based on chromatin remodeling through various histone modifications or through the intervention of non-coding RNAs (ncRNAs), have provided more information on the fibrotic process, and this could represent a promising path forward for the identification of innovative therapeutic strategies for organ fibrosis. In this review, we summarize current research on epigenetic mechanisms involved in organ fibrosis, with a focus on epigenetic regulation of EMP/EMT-dependent fibrosis.
Collapse
Affiliation(s)
- Margherita Sisto
- Department of Translational Biomedicine and Neuroscience (DiBraiN), Section of Human Anatomy and Histology, University of Bari, Piazza Giulio Cesare 1, I-70124 Bari, Italy;
| | | |
Collapse
|
|
13
|
Bartos K, Ramakrishnan SK, Braga-Lagache S, Hänzi B, Durussel F, Prakash Sridharan A, Zhu Y, Sheehan D, Hynes NE, Bonny O, Moor MB. Renal FGF23 signaling depends on redox protein Memo1 and promotes orthovanadate-sensitive protein phosphotyrosyl phosphatase activity. J Cell Commun Signal 2023; 17:705-722. [PMID: 36434320 PMCID: PMC10409928 DOI: 10.1007/s12079-022-00710-1] [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: 06/17/2022] [Accepted: 11/07/2022] [Indexed: 11/26/2022] Open
Abstract
Memo1 deletion in mice causes premature aging and an unbalanced metabolism partially resembling Fgf23 and Klotho loss-of-function animals. We report a role for Memo's redox function in renal FGF23-Klotho signaling using mice with postnatally induced Memo deficiency in the whole body (cKO). Memo cKO mice showed impaired FGF23-driven renal ERK phosphorylation and transcriptional responses. FGF23 actions involved activation of oxidation-sensitive protein phosphotyrosyl phosphatases in the kidney. Redox proteomics revealed excessive thiols of Rho-GDP dissociation inhibitor 1 (Rho-GDI1) in Memo cKO, and we detected a functional interaction between Memo's redox function and oxidation at Rho-GDI1 Cys79. In isolated cellular systems, Rho-GDI1 did not directly affect FGF23-driven cell signaling, but we detected disturbed Rho-GDI1 dependent small Rho-GTPase protein abundance and activity in the kidney of Memo cKO mice. Collectively, this study reveals previously unknown layers in the regulation of renal FGF23 signaling and connects Memo with the network of small Rho-GTPases.
Collapse
Affiliation(s)
- Katalin Bartos
- Department of Nephrology and Hypertension, Bern University Hospital and Department of Biomedical Research, University of Bern, Freiburgstrasse 15, 3010, Bern, Switzerland
- National Center of Competence in Research (NCCR) Kidney Control of Homeostasis (Kidney.CH), University of Zurich, Zurich, Switzerland
| | - Suresh Krishna Ramakrishnan
- National Center of Competence in Research (NCCR) Kidney Control of Homeostasis (Kidney.CH), University of Zurich, Zurich, Switzerland
- Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Sophie Braga-Lagache
- Proteomics and Mass Spectrometry Core Facility, Department for Biomedical Research (DBMR), University of Berne, Berne, Switzerland
| | - Barbara Hänzi
- Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Fanny Durussel
- Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Arjun Prakash Sridharan
- Proteomic Research Group, School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
| | - Yao Zhu
- Proteomic Research Group, School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
- School of Food and Nutritional Sciences, University College Cork, Cork, Ireland
| | - David Sheehan
- Proteomic Research Group, School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
- Department of Chemistry, College of Arts and Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Nancy E Hynes
- Friedrich Miescher Institute for Biomedical Research and University of Basel, Basel, Switzerland
| | - Olivier Bonny
- National Center of Competence in Research (NCCR) Kidney Control of Homeostasis (Kidney.CH), University of Zurich, Zurich, Switzerland
- Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
- Service of Nephrology, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland
- Service of Nephrology, Department of Medicine, Hôpital Fribourgeois, Fribourg, Switzerland
| | - Matthias B Moor
- Department of Nephrology and Hypertension, Bern University Hospital and Department of Biomedical Research, University of Bern, Freiburgstrasse 15, 3010, Bern, Switzerland.
- National Center of Competence in Research (NCCR) Kidney Control of Homeostasis (Kidney.CH), University of Zurich, Zurich, Switzerland.
- Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland.
| |
Collapse
|
|
14
|
Chi Z, Teng Y, Liu Y, Gao L, Yang J, Zhang Z. Association between klotho and non-alcoholic fatty liver disease and liver fibrosis based on the NHANES 2007-2016. Ann Hepatol 2023; 28:101125. [PMID: 37286168 DOI: 10.1016/j.aohep.2023.101125] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 05/24/2023] [Accepted: 05/29/2023] [Indexed: 06/09/2023]
Abstract
INTRODUCTION AND OBJECTIVES This study aims to explore the association between Klotho and Non-Alcoholic Fatty Liver Disease (NAFLD), a condition affecting millions worldwide. Klotho may have a protective effect against NAFLD mechanisms like inflammation, oxidative stress, and fibrosis. The study will use FLI and FIB-4 score to diagnose NAFLD in a large population for investigating the link between Klotho and NAFLD. MATERIALS AND METHODS The study aimed to explore the association between Klotho and NAFLD by measuring the α-Klotho protein levels in the participants' blood using ELISA. Patients with underlying chronic liver diseases were excluded. The severity of NAFLD was evaluated using FLI and FIB-4, and logistic regression models were used to analyze the data obtained from NHANES. Subgroup analyses were conducted to study Klotho's effect on hepatic steatosis and fibrosis in diverse subpopulations. RESULTS The study found that low levels of α-Klotho were associated with NAFLD, with ORs ranging from 0.72 to 0.83. However, high levels of α-Klotho were associated with NAFLD-related fibrosis. The Q4 group showed significant results in individuals aged 51 years or younger and in females. Non-Hispanic White ethnicity, education level of high school or above, non-smoking, non-hypertension, and non-diabetic groups showed negative correlations. CONCLUSIONS Our study suggests a potential correlation between α-Klotho levels in the blood and NAFLD in adult patients, especially among younger individuals, females and Non-Hispanic Whites. Elevated α-Klotho levels may have therapeutic benefits in treating NAFLD. Further research is required to validate these findings, but they provide new insights for managing this condition.
Collapse
Affiliation(s)
- Zhenfei Chi
- Liaoning University of Traditional Chinese Medicine, PR China
| | - Yun Teng
- Liaoning University of Traditional Chinese Medicine, PR China
| | - Yuting Liu
- Liaoning University of Traditional Chinese Medicine, PR China
| | - Lu Gao
- Liaoning University of Traditional Chinese Medicine, PR China
| | - Junhan Yang
- Liaoning University of Traditional Chinese Medicine, PR China
| | - Zhe Zhang
- Liaoning University of Traditional Chinese Medicine, PR China.
| |
Collapse
|
|
15
|
Wang YY, Lin YH, Wu VC, Lin YH, Huang CY, Ku WC, Sun CY. Decreased Klotho Expression Causes Accelerated Decline of Male Fecundity through Oxidative Injury in Murine Testis. Antioxidants (Basel) 2023; 12:1671. [PMID: 37759974 PMCID: PMC10526093 DOI: 10.3390/antiox12091671] [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: 07/13/2023] [Revised: 08/18/2023] [Accepted: 08/23/2023] [Indexed: 09/29/2023] Open
Abstract
Oxidative stress is the etiology for 30-80% of male patients affected by infertility, which is a major health problem worldwide. Klotho protein is an aging suppressor that functions as a humoral factor modulating various cellular processes including antioxidation and anti-inflammation, and its dysregulation leads to human pathologies. Male mice lacking Klotho are sterile, and decreased Klotho levels in the serum are observed in men suffering from infertility with lower sperm counts. However, the mechanism by which Klotho maintains healthy male fertility remains unclear. Klotho haplodeficiency (Kl+/-) accelerates fertility reduction by impairing sperm quality and spermatogenesis in Kl+/- mice. Testicular proteomic analysis revealed that loss of Klotho predominantly disturbed oxidation and the glutathione-related pathway. We further focused on the glutathione-S-transferase (GST) family which counteracts oxidative stress in most cell types and closely relates with fertility. Several GST proteins, including GSTP1, GSTO2, and GSTK1, were significantly downregulated, which subsequently resulted in increased levels of the lipid peroxidation product 4-hydroxynonenal and apoptosis in murine testis with low or no expression of Klotho. Taken together, the loss of one Kl allele accelerates male fecundity loss because diminished antioxidant capability induces oxidative injury in mice. This is the first study that highlights a connection between Klotho and GST proteins.
Collapse
Affiliation(s)
- Ya-Yun Wang
- Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City 242, Taiwan; (Y.-Y.W.); (Y.-H.L.)
| | - Ying-Hung Lin
- Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City 242, Taiwan; (Y.-Y.W.); (Y.-H.L.)
| | - Vin-Cent Wu
- Taiwan Consortium for Acute Kidney Injury and Renal Diseases (CAKs), Taipei 100, Taiwan;
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Yu-Hua Lin
- Department of Chemistry, Fu Jen Catholic University, New Taipei City 242, Taiwan;
- Division of Urology, Department of Surgery, Cardinal Tien Hospital, New Taipei City 231, Taiwan
| | - Chia-Yen Huang
- Gynecologic Cancer Center, Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei 106, Taiwan;
- School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan;
| | - Wei-Chi Ku
- School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan;
| | - Chiao-Yin Sun
- Division of Nephrology, Department of Internal Medicine, Keelung Chang Gung Memorial Hospital, Keelung 204, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| |
Collapse
|
|
16
|
Gluba-Sagr A, Franczyk B, Rysz-Górzyńska M, Ławiński J, Rysz J. The Role of miRNA in Renal Fibrosis Leading to Chronic Kidney Disease. Biomedicines 2023; 11:2358. [PMID: 37760798 PMCID: PMC10525803 DOI: 10.3390/biomedicines11092358] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 08/14/2023] [Accepted: 08/19/2023] [Indexed: 09/29/2023] Open
Abstract
Chronic kidney disease (CKD) is an important health concern that is expected to be the fifth most widespread cause of death worldwide by 2040. The presence of chronic inflammation, oxidative stress, ischemia, etc., stimulates the development and progression of CKD. Tubulointerstitial fibrosis is a common pathomechanism of renal dysfunction, irrespective of the primary origin of renal injury. With time, fibrosis leads to end-stage renal disease (ESRD). Many studies have demonstrated that microRNAs (miRNAs, miRs) are involved in the onset and development of fibrosis and CKD. miRNAs are vital regulators of some pathophysiological processes; therefore, their utility as therapeutic agents in various diseases has been suggested. Several miRNAs were demonstrated to participate in the development and progression of kidney disease. Since renal fibrosis is an important problem in chronic kidney disease, many scientists have focused on the determination of miRNAs associated with kidney fibrosis. In this review, we present the role of several miRNAs in renal fibrosis and the potential pathways involved. However, as well as those mentioned above, other miRs have also been suggested to play a role in this process in CKD. The reports concerning the impact of some miRNAs on fibrosis are conflicting, probably because the expression and regulation of miRNAs occur in a tissue- and even cell-dependent manner. Moreover, different assessment modes and populations have been used. There is a need for large studies and clinical trials to confirm the role of miRs in a clinical setting. miRNAs have great potential; thus, their analysis may improve diagnostic and therapeutic strategies.
Collapse
Affiliation(s)
- Anna Gluba-Sagr
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 90-549 Lodz, Poland
| | - Beata Franczyk
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 90-549 Lodz, Poland
| | - Magdalena Rysz-Górzyńska
- Department of Ophthalmology and Visual Rehabilitation, Medical University of Lodz, 90-549 Lodz, Poland
| | - Janusz Ławiński
- Department of Urology, Institute of Medical Sciences, College of Medical Sciences, University of Rzeszow, 35-055 Rzeszow, Poland
| | - Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 90-549 Lodz, Poland
| |
Collapse
|
|
17
|
Kim JE, Cho MH. Effects of Multiwall Carbon Nanotubes on Premature Kidney Aging: Biochemical and Histological Analysis. TOXICS 2023; 11:373. [PMID: 37112600 PMCID: PMC10143039 DOI: 10.3390/toxics11040373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 04/01/2023] [Accepted: 04/11/2023] [Indexed: 06/19/2023]
Abstract
Carbon nanotubes (CNTs) have gained much attention due to their superb properties, which make them promising options for the reinforcing composite materials with desirable mechanical properties. However, little is known about the linkage between lung exposure to nanomaterials and kidney disease. In this study, we compared the effects on the kidneys and aging for two different types of multiwall carbon nanotubes (MWCNTs): pristine MWCNTs (PMWCNTs) and acid-treated MWCNTs (TMWCNTs), with TMWCNTs being the preferred form for use as a composite material due to its superior dispersion properties. We used tracheal instillation and maximum tolerated dose (MTD) for both types of CNTs. MTD was determined as a 10% weight loss dose in a 3-month subchronic study, and the appropriate dosage for 1-year exposure was 0.1 mg/mouse. Serum and kidney samples were analyzed using ELISA, Western blot, and immunohistochemistry after 6 months and 1 year of treatment. PMWCNT-administered mice showed the activation of pathways for inflammation, apoptosis, and insufficient autophagy, as well as decreased serum Klotho levels and increased serum levels of DKK-1, FGF-23, and sclerostin, while TMWCNTs did not. Our study suggests that lung exposure to PMWCNTs can induce premature kidney aging and highlights a possible toxic effect of using MWCNTs on the kidneys in the industrial field, further highlighting that dispersibility can affect the toxicity of the nanotubes.
Collapse
Affiliation(s)
- Ji-Eun Kim
- Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Myung-Haing Cho
- Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea
- RNABIO, Seongnam 13201, Republic of Korea
| |
Collapse
|
|
18
|
Katayama IA, Huang Y, Garza AE, Brooks DL, Williams JS, Nascimento MM, Heimann JC, Pojoga LH. Longitudinal changes in blood pressure are preceded by changes in albuminuria and accelerated by increasing dietary sodium intake. Exp Gerontol 2023; 173:112114. [PMID: 36738979 PMCID: PMC10965150 DOI: 10.1016/j.exger.2023.112114] [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: 10/10/2022] [Revised: 01/31/2023] [Accepted: 02/01/2023] [Indexed: 02/06/2023]
Abstract
BACKGROUND Dietary sodium is a well-known risk factor for cardiovascular and renal disease; however, direct evidence of the longitudinal changes that occur with aging, and the influence of dietary sodium on the age-associated alterations are scarce. METHODS C57BL/6 mice were maintained for 13 months on a low (LS, 0.02 % Na+), normal (NS, 0.3 % Na+) or high (HS, 1.6 % Na+) salt diet. We assessed 1) the longitudinal trajectories for two markers of cardiovascular and renal dysfunction (blood pressure (BP) and albuminuria), as well as hormonal changes, and 2) end-of-study cardiac and renal parameters. RESULTS The effect of aging on BP and kidney damage did not reach significance levels in the LS group; however, relative to baseline, there were significant increases in these parameters for animals maintained on NS and HS diets, starting as early as month 7 and month 5, respectively. Furthermore, changes in albuminuria preceded the changes in BP relative to baseline, irrespective of the diet. Circulating aldosterone and plasma renin activity displayed the expected decreasing trends with age and dietary sodium loading. As compared to LS - higher dietary sodium consumption associated with increasing trends in left ventricular mass and volume indices, consistent with an eccentric dilated phenotype. Functional and molecular markers of kidney dysfunction displayed similar trends with increasing long-term sodium levels: higher renovascular resistance, increased glomerular volumes, as well as higher levels of renal angiotensin II type 1 and mineralocorticoid receptors, and lower renal Klotho levels. CONCLUSION Our study provides a timeline for the development of cardiorenal dysfunction with aging, and documents that increasing dietary salt accelerates the age-induced phenotypes. In addition, we propose albuminuria as a prognostic biomarker for the future development of hypertension. Last, we identified functional and molecular markers of renal dysfunction that associate with long-term dietary salt loading.
Collapse
Affiliation(s)
- Isis Akemi Katayama
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Laboratory of Experimental Hypertension, Department of Internal Medicine, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Yuefei Huang
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Amanda E Garza
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Danielle L Brooks
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jonathan S Williams
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Mariana M Nascimento
- Laboratory of Experimental Hypertension, Department of Internal Medicine, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Joel C Heimann
- Laboratory of Experimental Hypertension, Department of Internal Medicine, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Luminita H Pojoga
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
|
19
|
Donate-Correa J, Matos-Perdomo E, González-Luis A, Martín-Olivera A, Ortiz A, Mora-Fernández C, Navarro-González JF. The Value of Klotho in Kidney Transplantation. Transplantation 2023; 107:616-627. [PMID: 36253904 DOI: 10.1097/tp.0000000000004331] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Kidney transplant recipients have better survival rates and improved quality of life than long-term dialysis patients. However, delayed graft function, immunosuppressive therapy nephrotoxicity, and rejection episodes may compromise graft and patient survival. The KL gene is highly expressed in kidney tubular cells and encodes the antiaging and kidney-protective protein Klotho, which has membrane-anchored and soluble forms and regulates mineral metabolism. Klotho expression decreases during acute kidney injury or chronic kidney disease, and human chronic kidney disease shares features of accelerated aging with murine Klotho deficiency. In this work, we review clinical studies on the relationship between Klotho and kidney transplantation. Specifically, we address the dynamics of serum and kidney Klotho levels in donors and kidney transplant recipients, the role of Klotho as a marker of current graft function and graft outcomes, and the potential impact of Klotho on kidney protection in the transplantation context. A better understanding of the potential biomarker and therapeutic utility of Klotho in kidney transplant recipients may provide new insights into the control of graft function and new therapeutic strategies to preserve allograft function.
Collapse
Affiliation(s)
- Javier Donate-Correa
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, Santander, Spain
- Instituto de Tecnologías Biomédicas, University of La Laguna, Santa Cruz de Tenerife, Spain
| | - Emiliano Matos-Perdomo
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
- Doctoral and Graduate School, University of La Laguna, San Cristóbal de La Laguna, Tenerife, Spain
| | - Ainhoa González-Luis
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
- Instituto de Tecnologías Biomédicas, University of La Laguna, Santa Cruz de Tenerife, Spain
- Doctoral and Graduate School, University of La Laguna, San Cristóbal de La Laguna, Tenerife, Spain
| | - Alberto Martín-Olivera
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
- Instituto de Tecnologías Biomédicas, University of La Laguna, Santa Cruz de Tenerife, Spain
- Doctoral and Graduate School, University of La Laguna, San Cristóbal de La Laguna, Tenerife, Spain
| | - Alberto Ortiz
- Instituto de Investigación Sanitaria Fundación Jiménez-Díaz-Universidad Autónoma de Madrid, Madrid, Spain
- RICORS2040 (Red de Investigación Renal-RD21/0005/0013), Instituto de Salud Carlos III, Madrid, Spain
| | - Carmen Mora-Fernández
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, Santander, Spain
- RICORS2040 (Red de Investigación Renal-RD21/0005/0013), Instituto de Salud Carlos III, Madrid, Spain
| | - Juan F Navarro-González
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, Santander, Spain
- Instituto de Tecnologías Biomédicas, University of La Laguna, Santa Cruz de Tenerife, Spain
- RICORS2040 (Red de Investigación Renal-RD21/0005/0013), Instituto de Salud Carlos III, Madrid, Spain
| |
Collapse
|
|
20
|
Noonan ML, Ni P, Solis E, Marambio YG, Agoro R, Chu X, Wang Y, Gao H, Xuei X, Clinkenbeard EL, Jiang G, Liu S, Stegen S, Carmeliet G, Thompson WR, Liu Y, Wan J, White KE. Osteocyte Egln1/Phd2 links oxygen sensing and biomineralization via FGF23. Bone Res 2023; 11:7. [PMID: 36650133 PMCID: PMC9845350 DOI: 10.1038/s41413-022-00241-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 09/29/2022] [Accepted: 11/03/2022] [Indexed: 01/19/2023] Open
Abstract
Osteocytes act within a hypoxic environment to control key steps in bone formation. FGF23, a critical phosphate-regulating hormone, is stimulated by low oxygen/iron in acute and chronic diseases, however the molecular mechanisms directing this process remain unclear. Our goal was to identify the osteocyte factors responsible for FGF23 production driven by changes in oxygen/iron utilization. Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHI) which stabilize HIF transcription factors, increased Fgf23 in normal mice, as well as in osteocyte-like cells; in mice with conditional osteocyte Fgf23 deletion, circulating iFGF23 was suppressed. An inducible MSC cell line ('MPC2') underwent FG-4592 treatment and ATACseq/RNAseq, and demonstrated that differentiated osteocytes significantly increased HIF genomic accessibility versus progenitor cells. Integrative genomics also revealed increased prolyl hydroxylase Egln1 (Phd2) chromatin accessibility and expression, which was positively associated with osteocyte differentiation. In mice with chronic kidney disease (CKD), Phd1-3 enzymes were suppressed, consistent with FGF23 upregulation in this model. Conditional loss of Phd2 from osteocytes in vivo resulted in upregulated Fgf23, in line with our findings that the MPC2 cell line lacking Phd2 (CRISPR Phd2-KO cells) constitutively activated Fgf23 that was abolished by HIF1α blockade. In vitro, Phd2-KO cells lost iron-mediated suppression of Fgf23 and this activity was not compensated for by Phd1 or -3. In sum, osteocytes become adapted to oxygen/iron sensing during differentiation and are directly sensitive to bioavailable iron. Further, Phd2 is a critical mediator of osteocyte FGF23 production, thus our collective studies may provide new therapeutic targets for skeletal diseases involving disturbed oxygen/iron sensing.
Collapse
Affiliation(s)
- Megan L Noonan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Pu Ni
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Emmanuel Solis
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Yamil G Marambio
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Rafiou Agoro
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Xiaona Chu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Yue Wang
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Hongyu Gao
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Xiaoling Xuei
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Erica L Clinkenbeard
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Guanglong Jiang
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Sheng Liu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Steve Stegen
- Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, 3000, Leuven, Belgium
| | - Geert Carmeliet
- Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, 3000, Leuven, Belgium
| | - William R Thompson
- Department of Physical Therapy, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Yunlong Liu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Jun Wan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Kenneth E White
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
- Departments of Medicine/Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
| |
Collapse
|
|
21
|
Abraham CR, Li A. Aging-suppressor Klotho: Prospects in diagnostics and therapeutics. Ageing Res Rev 2022; 82:101766. [PMID: 36283617 DOI: 10.1016/j.arr.2022.101766] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 10/16/2022] [Accepted: 10/17/2022] [Indexed: 01/31/2023]
Abstract
INTRODUCTION The protein Klotho (KL) was first discovered in KL-deficient mice, which developed a syndrome similar to premature aging in humans. Since then, KL has been implicated in multiple molecular signaling pathways and diseases. KL has been shown to have anti-aging, healthspan and lifespan extending, cognitive enhancing, anti-oxidative, anti-inflammatory, and anti-tumor properties. KL levels decrease with age and in many diseases. Therefore, it has been of great interest to develop a KL-boosting or restoring drug, or to supplement endogenous Klotho with exogenous Klotho genetic material or recombinant Klotho protein, and to use KL levels in the body as a marker for the efficacy of such drugs and as a biomarker for the diagnosis and management of diseases. OBJECTIVE The goal of this study was to provide a comprehensive review of KL levels across age groups in individuals who are healthy or have certain health conditions, using four sources: blood, cerebrospinal fluid, urine, and whole biopsy/necropsy tissue. By doing so, baseline KL levels can be identified across the lifespan, in the absence or presence of disease. In turn, these findings can be used to guide the development of future KL-based therapeutics and biomarkers, which will heavily rely on an individual's baseline KL range to be efficacious. METHODS A total of 65 studies were collected primarily using the PubMed database. Research articles that were published up to April 2022 were included. Statistical analysis was conducted using RStudio. RESULTS Mean and median blood KL levels in healthy individuals, mean blood KL levels in individuals with renal conditions, and mean blood KL levels in individuals with metabolic or endocrine conditions were shown to decrease with age. Similarly, CSF KL levels in patients with AD also declined compared with age-matched controls. CONCLUSIONS The present study confirms the trend that KL levels in blood decrease with age in humans, among those who are healthy, and even further among those with renal and endocrine/metabolic illnesses. Further, by drawing this trend from multiple published works, we were able to provide a general idea of baseline KL ranges, specifically in blood in these populations. These data add to the current knowledge on normal KL levels in the body and how they change with time and in disease, and can potentially support efforts to create KL-based treatments and screening tools to better manage aging, renal, and metabolic/endocrine diseases.
Collapse
Affiliation(s)
- Carmela R Abraham
- Department of Biochemistry, Boston University School of Medicine, USA; Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, USA.
| | - Anne Li
- Division of Graduate Medical Sciences, Boston University School of Medicine, Boston, MA, USA.
| |
Collapse
|
|
22
|
Epidemiology and risk of cardiovascular disease in populations with chronic kidney disease. Nat Rev Nephrol 2022; 18:696-707. [DOI: 10.1038/s41581-022-00616-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/26/2022] [Indexed: 11/08/2022]
|
|
23
|
Kaka N, Sethi Y, Patel N, Kaiwan O, Al-Inaya Y, Manchanda K, Uniyal N. Endocrine manifestations of chronic kidney disease and their evolving management: A systematic review. Dis Mon 2022; 68:101466. [PMID: 35965104 DOI: 10.1016/j.disamonth.2022.101466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Chronic Kidney Disease (CKD) shows a wide range of renal abnormalities including the excretory, metabolic, endocrine, and homeostatic function of the kidney. The prognostic impact of the 'endocrine manifestations' which are often overlooked by clinicians cannot be overstated. METHODS AND OBJECTIVES A systematic review was attempted to provide a comprehensive overview of all endocrine abnormalities of CKD and their evolving principles of management, searching databases of PubMed, Embase, and Scopus and covering the literature between 2002 and 2022. RESULTS The endocrine derangements in CKD can be attributed to a myriad of pathologic processes, in particular decreased clearance, impaired endogenous hormone production, uremia-induced cellular dysfunction, and activation of systemic inflammatory pathways. The major disorders include anemia, hyperprolactinemia, insulin resistance, reproductive hormone deficiency, thyroid hormone deficiency, and serum FGF (Fibroblast Growth Factor) alteration. Long-term effects of CKD also include malnutrition and increased cardiovascular risk. The recent times have unveiled their detailed pathogenesis and have seen an evolution in the principles of management which necessitates a revision of current guidelines. CONCLUSION Increased advertence regarding the pathology, impact, and management of these endocrine derangements can help in reducing morbidity as well as mortality in the CKD patients by allowing prompt individualized treatment. Moreover, with timely and appropriate intervention, a long-term reduction in complications, as well as an enhanced quality of life, can be achieved in patients with CKD.
Collapse
Affiliation(s)
- Nirja Kaka
- GMERS Medical College, Himmatnagar, Gujarat 382007, India
| | - Yashendra Sethi
- Department of Medicine, Government Doon Medical College, Dehradun, Uttarakhand, India
| | - Neil Patel
- GMERS Medical College, Himmatnagar, Gujarat 382007, India.
| | | | | | | | - Nidhi Uniyal
- Department of Medicine, Government Doon Medical College, Dehradun, Uttarakhand, India
| |
Collapse
|
|
24
|
Baccam GC, Xie J, Jin X, Park H, Wang B, Husson H, Ibraghimov-Beskrovnaya O, Huang CL. Glucosylceramide synthase inhibition protects against cardiac hypertrophy in chronic kidney disease. Sci Rep 2022; 12:9340. [PMID: 35660779 PMCID: PMC9167280 DOI: 10.1038/s41598-022-13390-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 05/09/2022] [Indexed: 11/20/2022] Open
Abstract
A significant population of patients with chronic kidney disease (CKD) develops cardiac hypertrophy, which can lead to heart failure and sudden cardiac death. Soluble klotho (sKL), the shed ectodomain of the transmembrane protein klotho, protects the heart against hypertrophic growth. We have shown that sKL protects the heart by regulating the formation and function of lipid rafts by targeting the sialic acid moiety of gangliosides, GM1/GM3. Reduction in circulating sKL contributes to an increased risk of cardiac hypertrophy in mice. sKL replacement therapy has been considered but its use is limited by the inability to mass produce the protein. Therefore, alternative methods to protect the heart are proposed. Glucosylation of ceramide catalyzed by glucosylceramide synthase is the entry step for the formation of gangliosides. Here we show that oral administration of a glucosylceramide synthase inhibitor (GCSi) reduces plasma and heart tissue glycosphingolipids, including gangliosides. Administration of GCSi is protective in two mouse models of cardiac stress-induction, one with isoproterenol overstimulation and the other with 5/6 nephrectomy-induced CKD. Treatment with GCSi does not alter the severity of renal dysfunction and hypertension in CKD. These results provide proof of principle for targeting glucosylceramide synthase to decrease gangliosides as a treatment for cardiac hypertrophy. They also support the hypothesis that sKL protects the heart by targeting gangliosides.
Collapse
Affiliation(s)
- Gabriel C Baccam
- Division of Nephrology, Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, E300 GH, Iowa City, IA, 52242-1081, USA
| | - Jian Xie
- Division of Nephrology, Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, E300 GH, Iowa City, IA, 52242-1081, USA
| | - Xin Jin
- Division of Nephrology, Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, E300 GH, Iowa City, IA, 52242-1081, USA
| | - Hyejung Park
- US Early Development, Synthetics Platform, Global CMC Development, Sanofi, Waltham, MA, 02451, USA
| | - Bing Wang
- US Early Development, Synthetics Platform, Global CMC Development, Sanofi, Waltham, MA, 02451, USA
| | - Hervé Husson
- Genomic Medicine Unit, Sanofi, Framingham, MA, 01701, USA
| | - Oxana Ibraghimov-Beskrovnaya
- Rare and Neurologic Diseases, Sanofi, Framingham, MA, 01701, USA
- Dyne Therapeutics, 1560 Trapelo Road, Waltham, MA, 20451, USA
| | - Chou-Long Huang
- Division of Nephrology, Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, E300 GH, Iowa City, IA, 52242-1081, USA.
| |
Collapse
|
|
25
|
Kusumi K, Kremsdorf R, Kakajiwala A, Mahan JD. Pediatric Mineral and Bone Disorder of Chronic Kidney Disease and Cardiovascular Disease. Adv Chronic Kidney Dis 2022; 29:275-282. [PMID: 36084974 DOI: 10.1053/j.ackd.2022.04.002] [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: 09/02/2021] [Revised: 03/29/2022] [Accepted: 04/05/2022] [Indexed: 11/11/2022]
Abstract
Chronic kidney disease is common and causes significant morbidity including shortened lifespans and decrease in quality of life for patients. The major cause of mortality in chronic kidney disease is cardiovascular disease. Cardiovascular disease within the chronic kidney disease population is closely tied with disordered calcium and phosphorus metabolism and driven in part by renal bone disease. The complex nature of renal, bone, and cardiovascular diseases was renamed as mineral and bone disorder of chronic kidney disease to encompass how bone disease drives vascular calcification and contributes to the development of long-term cardiovascular disease, and recent data suggest that managing bone disease well can augment and improve cardiovascular disease status. Pediatric nephrologists have additional obstacles in optimal mineral and bone disorder of chronic kidney disease management such as linear growth and skeletal maturation. In this article, we will discuss cardiovascular and bone diseases in chronic kidney disease and end-stage kidney disease patients with a focus on pediatric issues and concerns.
Collapse
Affiliation(s)
- Kirsten Kusumi
- Department of Pediatric Nephrology, Akron Children's Hospital, Akron, OH.
| | - Robin Kremsdorf
- Pediatric Nephrology and Hypertension, Hasbro Children's Hospital, Providence, RI
| | - Aadil Kakajiwala
- Departments of Pediatric Critical Care Medicine and Nephrology, Children's National Hospital, Washington, DC
| | - John D Mahan
- Division of Nephrology and Hypertension at Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH
| |
Collapse
|
|
26
|
Urine-Derived Stem Cell-Secreted Klotho Plays a Crucial Role in the HK-2 Fibrosis Model by Inhibiting the TGF-β Signaling Pathway. Int J Mol Sci 2022; 23:ijms23095012. [PMID: 35563402 PMCID: PMC9105028 DOI: 10.3390/ijms23095012] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 04/28/2022] [Accepted: 04/28/2022] [Indexed: 02/01/2023] Open
Abstract
Renal fibrosis is an irreversible and progressive process that causes severe dysfunction in chronic kidney disease (CKD). The progression of CKD stages is highly associated with a gradual reduction in serum Klotho levels. We focused on Klotho protein as a key therapeutic factor against CKD. Urine-derived stem cells (UDSCs) have been identified as a novel stem cell source for kidney regeneration and CKD treatment because of their kidney tissue-specific origin. However, the relationship between UDSCs and Klotho in the kidneys is not yet known. In this study, we discovered that UDSCs were stem cells that expressed Klotho protein more strongly than other mesenchymal stem cells (MSCs). UDSCs also suppressed fibrosis by inhibiting transforming growth factor (TGF)-β in HK-2 human renal proximal tubule cells in an in vitro model. Klotho siRNA silencing reduced the TGF-inhibiting ability of UDSCs. Here, we suggest an alternative cell source that can overcome the limitations of MSCs through the synergetic effect of the origin specificity of UDSCs and the anti-fibrotic effect of Klotho.
Collapse
|
|
27
|
Sobh MM, Abdalbary M, Elnagar S, Nagy E, Elshabrawy N, Abdelsalam M, Asadipooya K, El-Husseini A. Secondary Osteoporosis and Metabolic Bone Diseases. J Clin Med 2022; 11:2382. [PMID: 35566509 PMCID: PMC9102221 DOI: 10.3390/jcm11092382] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/17/2022] [Accepted: 04/20/2022] [Indexed: 02/04/2023] Open
Abstract
Fragility fracture is a worldwide problem and a main cause of disability and impaired quality of life. It is primarily caused by osteoporosis, characterized by impaired bone quantity and or quality. Proper diagnosis of osteoporosis is essential for prevention of fragility fractures. Osteoporosis can be primary in postmenopausal women because of estrogen deficiency. Secondary forms of osteoporosis are not uncommon in both men and women. Most systemic illnesses and organ dysfunction can lead to osteoporosis. The kidney plays a crucial role in maintaining physiological bone homeostasis by controlling minerals, electrolytes, acid-base, vitamin D and parathyroid function. Chronic kidney disease with its uremic milieu disturbs this balance, leading to renal osteodystrophy. Diabetes mellitus represents the most common secondary cause of osteoporosis. Thyroid and parathyroid disorders can dysregulate the osteoblast/osteoclast functions. Gastrointestinal disorders, malnutrition and malabsorption can result in mineral and vitamin D deficiencies and bone loss. Patients with chronic liver disease have a higher risk of fracture due to hepatic osteodystrophy. Proinflammatory cytokines in infectious, autoimmune, and hematological disorders can stimulate osteoclastogenesis, leading to osteoporosis. Moreover, drug-induced osteoporosis is not uncommon. In this review, we focus on causes, pathogenesis, and management of secondary osteoporosis.
Collapse
Affiliation(s)
- Mahmoud M. Sobh
- Mansoura Nephrology and Dialysis Unit, Mansoura University, Mansoura 35516, Egypt; (M.M.S.); (M.A.); (S.E.); (E.N.); (N.E.); (M.A.)
| | - Mohamed Abdalbary
- Mansoura Nephrology and Dialysis Unit, Mansoura University, Mansoura 35516, Egypt; (M.M.S.); (M.A.); (S.E.); (E.N.); (N.E.); (M.A.)
- Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Lexington, KY 40506, USA
| | - Sherouk Elnagar
- Mansoura Nephrology and Dialysis Unit, Mansoura University, Mansoura 35516, Egypt; (M.M.S.); (M.A.); (S.E.); (E.N.); (N.E.); (M.A.)
| | - Eman Nagy
- Mansoura Nephrology and Dialysis Unit, Mansoura University, Mansoura 35516, Egypt; (M.M.S.); (M.A.); (S.E.); (E.N.); (N.E.); (M.A.)
| | - Nehal Elshabrawy
- Mansoura Nephrology and Dialysis Unit, Mansoura University, Mansoura 35516, Egypt; (M.M.S.); (M.A.); (S.E.); (E.N.); (N.E.); (M.A.)
| | - Mostafa Abdelsalam
- Mansoura Nephrology and Dialysis Unit, Mansoura University, Mansoura 35516, Egypt; (M.M.S.); (M.A.); (S.E.); (E.N.); (N.E.); (M.A.)
| | - Kamyar Asadipooya
- Division of Endocrinology, University of Kentucky, Lexington, KY 40506, USA;
| | - Amr El-Husseini
- Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Lexington, KY 40506, USA
| |
Collapse
|
|
28
|
Fakhar M, Najumuddin, Zahid S, Rashid S. Structural basis of Klotho binding to VEGFR2 and TRPC1 and repurposing calcium channel blockers as TRPC1 antagonists for the treatment of age-related cardiac hypertrophy. Arch Biochem Biophys 2022; 719:109171. [DOI: 10.1016/j.abb.2022.109171] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 12/13/2021] [Accepted: 02/28/2022] [Indexed: 11/15/2022]
|
|
29
|
Lee HJ, Choi JY, Lee J, Kim D, Min JY, Min KB. Association between serum uric acid and α-klotho protein levels in the middle-aged population. Aging (Albany NY) 2022; 14:2537-2547. [PMID: 35351833 PMCID: PMC9004568 DOI: 10.18632/aging.203987] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 03/14/2022] [Indexed: 11/25/2022]
Abstract
This study investigated the association between hyperuricemia and serum klotho protein levels in a representative sample of adults in the United States. We included 11,734 adults aged 40–80 years with available data of serum klotho, uric acid, covariates related to demographics, health behavior-related variables, and medical histories. Hyperuricemia was defined as a serum uric acid level of ≥7.0 mg/dL in men and ≥6.0 mg/dL in women. The geometric mean of serum klotho was 806.5 pg/mL (95% confidence interval: 801.7–811.4). The log-klotho level was negatively correlated with the uric acid level (r = −0.154; p < 0.0001). After adjustment for potential covariates, each one-unit increase in uric acid was significantly associated with a decrease in the log-klotho level (adjusted beta = −0.028; p < 0.0001). Compared with subjects without hyperuricemia, those with hyperuricemia had significantly lower serum klotho levels (adjusted beta = −0.062; p < 0.0001). We found a significant inverse association between serum uric acid and serum klotho levels in the general population, that is, an increase in serum uric acid levels was associated with a decrease in klotho levels. This finding suggests that loss of klotho may be due to the progression of hyperuricemia or, subsequently, gout.
Collapse
Affiliation(s)
- Hyo-Jung Lee
- Department of Preventive Medicine, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Ju-Young Choi
- Department of Preventive Medicine, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Jaeho Lee
- Department of Preventive Medicine, College of Medicine, Seoul National University, Seoul, Republic of Korea.,Institute Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Republic of Korea
| | - Donghoon Kim
- Department of Preventive Medicine, College of Medicine, Seoul National University, Seoul, Republic of Korea.,Institute Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Republic of Korea
| | - Jin-Young Min
- Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, Republic of Korea
| | - Kyoung-Bok Min
- Department of Preventive Medicine, College of Medicine, Seoul National University, Seoul, Republic of Korea.,Institute of Health Policy and Management, Medical Research Center, Seoul National University, Seoul, Republic of Korea.,Institute Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Republic of Korea
| |
Collapse
|
|
30
|
Tanaka SI, Fujioka Y, Tsujino T, Ishida T, Hirata KI. Association between urinary N-acetyl-β-glucosaminidase activity–urinary creatinine concentration ratio and risk of disability and all-cause mortality. PLoS One 2022; 17:e0265637. [PMID: 35333903 PMCID: PMC8956177 DOI: 10.1371/journal.pone.0265637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 03/07/2022] [Indexed: 12/03/2022] Open
Abstract
Background Recent studies have suggested that chronic kidney disease is associated with cardiovascular disease, dementia, and frailty, all of which cause disability and early death. We investigated whether increased activity of urinary N-acetyl-β-glucosaminidase (NAG), a marker of kidney injury, is associated with risk of disability or all-cause mortality in a general population. Methods Follow-up data from the Hidaka Cohort Study, a population-based cohort study of members of a Japanese rural community, were obtained via questionnaires completed by participants or their relatives. Multivariable analyses were used to investigate relations between urinary NAG activity–urinary creatinine concentration ratio and risk of disability or all-cause mortality. Results A total of 1182 participants were followed up for a median of 12.4 years. The endpoints were receipt of support under the public long-term care insurance program, and all-cause mortality. A total of 122 participants (10.3%) were reported to be receiving long-term care and 230 (19.5%) had died. After adjustment for cardiovascular risk factors along with physical activity, and using the quartile 1 results as a reference, the odds ratio (OR) for disability was 2.12 [95% confidence interval (95% confidence interval [CI]), 1.04–4.33; p = 0.038) and the hazard ratio (HR) for all-cause mortality was 1.65 (95% CI, 1.05–2.62; p = 0.031) in participants with urinary NAG/creatinine ratio in quartile 4. Similar results were obtained in participants without proteinuria: OR for disability, 2.46 (95% CI, 1.18–5.16; p = 0.017); and HR for all-cause mortality, 1.62 (95% CI, 1.00–2.63; p = 0.049). Conclusions Increased urinary NAG/creatinine ratio was associated with risk of disability or all-cause mortality in a general population.
Collapse
Affiliation(s)
- Shin-ichiro Tanaka
- Department of Internal Medicine, Toyooka Hospital Hidaka Medical Center, Toyooka, Hyogo, Japan
- * E-mail:
| | - Yoshio Fujioka
- Division of Clinical Nutrition, Faculty of Nutrition, Kobe Gakuin University, Kobe, Japan
| | - Takeshi Tsujino
- Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan
| | - Tatsuro Ishida
- Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Ken-ichi Hirata
- Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| |
Collapse
|
|
31
|
Coppola A, Vigorito C, Lombari P, Martínez YG, Borriello M, Trepiccione F, Ingrosso D, Perna AF. Uremic Toxin Lanthionine Induces Endothelial Cell Mineralization In Vitro. Biomedicines 2022; 10:biomedicines10020444. [PMID: 35203651 PMCID: PMC8962276 DOI: 10.3390/biomedicines10020444] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/10/2022] [Accepted: 02/11/2022] [Indexed: 01/03/2023] Open
Abstract
Vascular calcification (VC) is a pathological event caused by the unusual deposition of minerals in the vascular system, representing the leading cause of cardiovascular mortality in chronic kidney disease (CKD). In CKD, the deregulation of calcium and phosphate metabolism, along with the effect of several uremic toxins, act as key processes conveying altered mineralization. In this work, we tested the ability of lanthionine, a novel uremic toxin, to promote calcification in human endothelial cell cultures (Ea.hy926). We evaluated the effects of lanthionine, at a concentration similar to that actually detected in CKD patients, alone and under pro-calcifying culture conditions using calcium and phosphate. In pro-calcific culture conditions, lanthionine increased both the intracellular and extracellular calcium content and induced the expression of Bone Morphogenetic Protein 2 (BMP2) and RUNX Family Transcription Factor 2 (RUNX2). Lanthionine treatment, in pro-calcifying conditions, raised levels of tissue-nonspecific alkaline phosphatase (ALPL), whose expression also overlapped with Dickkopf WNT Signaling Pathway Inhibitor 1 (DKK1) gene expression, suggesting a possible role of the latter gene in the activation of ALPL. In addition, treatment with lanthionine alone or in combination with calcium and phosphate reduced Inorganic Pyrophosphate Transport Regulator (ANKH) gene expression, a protective factor toward the mineralizing process. Moreover, lanthionine in a pro-calcifying condition induced the activation of ERK1/2, which is not associated with an increase in DKK1 protein levels. Our data underscored a link between mineral disease and the alterations of sulfur amino acid metabolisms at a cell and molecular level. These results set the basis for the understanding of the link between uremic toxins and mineral-bone disorder during CKD progression.
Collapse
Affiliation(s)
- Annapaola Coppola
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio 7, 80138 Naples, Italy; (A.C.); (P.L.); (M.B.)
| | - Carmela Vigorito
- Department of Translational Medical Science University of Campania “Luigi Vanvitelli”, Via Pansini, Bldg 17, 80131 Naples, Italy; (C.V.); (Y.G.M.); (F.T.)
| | - Patrizia Lombari
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio 7, 80138 Naples, Italy; (A.C.); (P.L.); (M.B.)
- Department of Translational Medical Science University of Campania “Luigi Vanvitelli”, Via Pansini, Bldg 17, 80131 Naples, Italy; (C.V.); (Y.G.M.); (F.T.)
| | - Yuselys García Martínez
- Department of Translational Medical Science University of Campania “Luigi Vanvitelli”, Via Pansini, Bldg 17, 80131 Naples, Italy; (C.V.); (Y.G.M.); (F.T.)
| | - Margherita Borriello
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio 7, 80138 Naples, Italy; (A.C.); (P.L.); (M.B.)
| | - Francesco Trepiccione
- Department of Translational Medical Science University of Campania “Luigi Vanvitelli”, Via Pansini, Bldg 17, 80131 Naples, Italy; (C.V.); (Y.G.M.); (F.T.)
| | - Diego Ingrosso
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio 7, 80138 Naples, Italy; (A.C.); (P.L.); (M.B.)
- Correspondence: (D.I.); (A.F.P.)
| | - Alessandra F. Perna
- Department of Translational Medical Science University of Campania “Luigi Vanvitelli”, Via Pansini, Bldg 17, 80131 Naples, Italy; (C.V.); (Y.G.M.); (F.T.)
- Correspondence: (D.I.); (A.F.P.)
| |
Collapse
|
|
32
|
Hamdy M, Shaheen I, Seif El Din H, Ali B, Abdel Dayem O. Klotho Level as a Marker of Low Bone Mineral Density in Egyptian Sickle Cell Disease Patients. J Pediatr Hematol Oncol 2022; 44:e40-e45. [PMID: 34054039 DOI: 10.1097/mph.0000000000002231] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 05/06/2021] [Indexed: 11/26/2022]
Abstract
Bone involvement of sickle cell disease (SCD) patients varies from acute clinical manifestations of painful vaso-occlusive crises or osteomyelitis to more chronic affection of bone mineral density (BMD) and debilitating osteonecrosis and osteoporosis. Secreted klotho protein is involved in calcium (Ca) reabsorption in the kidney. This study aimed to measure serum klotho levels in children with SCD to determine the possibility of using it as a marker of low BMD in children with SCD in correlation with a dual-energy radiograph absorptiometry scan. This study included 60 sickle disease patients and 30 age-matched and sex-matched control participants without SCD. A highly statistically significant difference was found between patients with normal BMD and those with low BMD, with serum Ca and klotho levels being lower in the latter group. Klotho serum level correlated positively with both serum Ca and BMD. Serum klotho level showed 94.9% sensitivity and 95.2% specificity in the detection of low BMD. Both serum Ca and klotho serum levels may be useful markers for detection of low BMD related to SCD with high sensitivity and specificity; however, klotho may be a better indicator as it is less affected by the nutritional and endocrinal status of patients or by intake of Ca supplements.
Collapse
|
|
33
|
Gong Z, Banchs PAP, Liu Y, Fu H, Arena VC, Forno E, Libman I, Ho J, Muzumdar R. Serum α-KL, a potential early marker of diabetes complications in youth with T1D, is regulated by miRNA 192. Front Endocrinol (Lausanne) 2022; 13:937093. [PMID: 35992154 PMCID: PMC9388782 DOI: 10.3389/fendo.2022.937093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 07/07/2022] [Indexed: 12/29/2022] Open
Abstract
Despite the wealth of information on biomarkers of diabetes complications in adults with type 1 diabetes, data in the pediatric population is limited. Diabetic nephropathy (DN), the leading cause of mortality in type 1 diabetes T1D), could be potentially missed in youth, as albuminuria, the current "gold" standard, may be transient and may not reflect permanent renal impairment. Soluble alpha KL has emerged as a potential marker of early diabetic nephropathy. Seventy-nine pediatric patients with type 1 diabetes meeting ISPAD criteria for nephropathy screening were consecutively recruited (90% Caucasian, 51% male, mean age 16.1 ± 3.1 years, duration of T1D 7.2 ± 3.9 years, 2-year average HbA1c 8.0 ± 1.3%, and serum and urine samples were collected for analysis. Serum Klotho (KL) and circulating miRNA levels of select miRNA involved in the pathogenesis of DN were estimated. KL had a strong inverse correlation with diabetes duration and HbA1c, two important risk factors in the development of diabetes complications. Serum miR-192 were negatively associated with KL among children with prolonged duration of diabetes (≥12 years) after adjustment for age and sex. In cell culture, overexpression of miR-192 significantly downregulated KL mRNA and protein levels, and reduced KL levels in the media. miR-192 mimic reduced luciferase activity in a reporter containing the KL 3' UTR (60% compared to controls, p<0.01), and the inhibitor rescued it. Deletion of a potential binding site for miR-192 in the KL 3'UTR completely abolished the effect of miR-192 in the reporter assay, suggesting that KL is a direct target gene of miR-192. Overexpression of miR-192 significantly increased oxidative stress (MDA) and expression of inflammatory and senescence markers IL-6 and p16. Inhibition of miR-192 significantly reduced levels of MDA, IL-6 and p16. In summary, we demonstrate an increase in miR-192 and a decrease in KL levels in children with prolonged duration of T1D. We demonstrate a novel role for miR-192 in directly regulating KL levels, and through that, senescence and oxidative stress, key pathological processes in the development of DN. miR-192 and/or KL levels are altered with severity and duration of diabetes and could serve as early biomarkers for DN.
Collapse
Affiliation(s)
- Zhenwei Gong
- University of Pittsburgh Medical Center, Children’s Hospital of Pittsburgh, PA, United States
- Department of Pediatrics, University of Pittsburgh, PA, United States
| | - Pedro A. Pagán Banchs
- University of Pittsburgh Medical Center, Children’s Hospital of Pittsburgh, PA, United States
- Department of Pediatrics, University of Pittsburgh, PA, United States
| | - Ye Liu
- University of Pittsburgh Medical Center, Children’s Hospital of Pittsburgh, PA, United States
| | - Haoyi Fu
- Department of Biostatistics, School of Public Health, University of Pittsburgh, PA, United States
| | - Vincent C. Arena
- Department of Biostatistics, School of Public Health, University of Pittsburgh, PA, United States
| | - Erick Forno
- University of Pittsburgh Medical Center, Children’s Hospital of Pittsburgh, PA, United States
- Department of Pediatrics, University of Pittsburgh, PA, United States
| | - Ingrid Libman
- University of Pittsburgh Medical Center, Children’s Hospital of Pittsburgh, PA, United States
- Department of Pediatrics, University of Pittsburgh, PA, United States
| | - Jacqueline Ho
- University of Pittsburgh Medical Center, Children’s Hospital of Pittsburgh, PA, United States
- Department of Pediatrics, University of Pittsburgh, PA, United States
| | - Radhika Muzumdar
- University of Pittsburgh Medical Center, Children’s Hospital of Pittsburgh, PA, United States
- Department of Pediatrics, University of Pittsburgh, PA, United States
- *Correspondence: Radhika Muzumdar,
| |
Collapse
|
|
34
|
Franco ML, Beyerstedt S, Rangel ÉB. Klotho and Mesenchymal Stem Cells: A Review on Cell and Gene Therapy for Chronic Kidney Disease and Acute Kidney Disease. Pharmaceutics 2021; 14:pharmaceutics14010011. [PMID: 35056905 PMCID: PMC8778857 DOI: 10.3390/pharmaceutics14010011] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/16/2021] [Accepted: 12/17/2021] [Indexed: 02/07/2023] Open
Abstract
Chronic kidney disease (CKD) and acute kidney injury (AKI) are public health problems, and their prevalence rates have increased with the aging of the population. They are associated with the presence of comorbidities, in particular diabetes mellitus and hypertension, resulting in a high financial burden for the health system. Studies have indicated Klotho as a promising therapeutic approach for these conditions. Klotho reduces inflammation, oxidative stress and fibrosis and counter-regulates the renin-angiotensin-aldosterone system. In CKD and AKI, Klotho expression is downregulated from early stages and correlates with disease progression. Therefore, the restoration of its levels, through exogenous or endogenous pathways, has renoprotective effects. An important strategy for administering Klotho is through mesenchymal stem cells (MSCs). In summary, this review comprises in vitro and in vivo studies on the therapeutic potential of Klotho for the treatment of CKD and AKI through the administration of MSCs.
Collapse
Affiliation(s)
- Marcella Liciani Franco
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, Sao Paulo 05652-900, Brazil; (M.L.F.); (S.B.)
| | - Stephany Beyerstedt
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, Sao Paulo 05652-900, Brazil; (M.L.F.); (S.B.)
| | - Érika Bevilaqua Rangel
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, Sao Paulo 05652-900, Brazil; (M.L.F.); (S.B.)
- Nephrology Division, Federal University of São Paulo, Sao Paulo 04038-901, Brazil
- Correspondence: ; Tel.: +55-11-2151-2148
| |
Collapse
|
|
35
|
Fotheringham AK, Solon-Biet SM, Bielefeldt-Ohmann H, McCarthy DA, McMahon AC, Ruohonen K, Li I, Sullivan MA, Whiddett RO, Borg DJ, Cogger VC, Ballard WO, Turner N, Melvin RG, Raubenheimer D, Le Couteur DG, Simpson SJ, Forbes JM. Kidney disease risk factors do not explain impacts of low dietary protein on kidney function and structure. iScience 2021; 24:103308. [PMID: 34820603 PMCID: PMC8602032 DOI: 10.1016/j.isci.2021.103308] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 04/29/2021] [Accepted: 10/15/2021] [Indexed: 02/06/2023] Open
Abstract
The kidneys balance many byproducts of the metabolism of dietary components. Previous studies examining dietary effects on kidney health are generally of short duration and manipulate a single macronutrient. Here, kidney function and structure were examined in C57BL/6J mice randomized to consume one of a spectrum of macronutrient combinations (protein [5%–60%], carbohydrate [20%–75%], and fat [20%–75%]) from weaning to late-middle age (15 months). Individual and interactive impacts of macronutrients on kidney health were modeled. Dietary protein had the greatest influence on kidney function, where chronic low protein intake decreased glomerular filtration rates and kidney mass, whereas it increased kidney immune infiltration and structural injury. Kidney outcomes did not align with cardiometabolic risk factors including glucose intolerance, overweight/obesity, dyslipidemia, and hypertension in mice with chronic low protein consumption. This study highlights that protein intake over a lifespan is an important determinant of kidney function independent of cardiometabolic changes.
Chronic high macronutrient intake from any source increases kidney function (GFR) Low protein intake led to greater kidney tubular structural injury and inflammation Lower protein intake decreased kidney mass and glomerular filtration capacity Kidney outcomes did not align with longevity or cardiometabolic outcomes
Collapse
Affiliation(s)
- Amelia K Fotheringham
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane 4072, QLD, Australia.,Faculty of Medicine, University of Queensland, Brisbane 4067, QLD, Australia
| | - Samantha M Solon-Biet
- Charles Perkins Centre, University of Sydney, Sydney 2006, NSW, Australia.,School of Medical Sciences, University of Sydney, Sydney 2006, NSW, Australia
| | - Helle Bielefeldt-Ohmann
- School of Veterinary Science, University of Queensland, Gatton Campus, Gatton 4343, QLD, Australia.,School of Chemistry & Molecular Biosciences, University of Queensland, Brisbane 4067, QLD, Australia
| | - Domenica A McCarthy
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane 4072, QLD, Australia
| | - Aisling C McMahon
- Charles Perkins Centre, University of Sydney, Sydney 2006, NSW, Australia.,Centre for Education and Research on Aging, and Aging and Alzheimer's Institute, Concord Hospital, Sydney 2139, NSW, Australia.,ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney 2139, NSW, Australia
| | - Kari Ruohonen
- Animal Nutrition and Health, Cargill, Sandnes, Norway
| | - Isaac Li
- Faculty of Medicine, University of Queensland, Brisbane 4067, QLD, Australia
| | - Mitchell A Sullivan
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane 4072, QLD, Australia
| | - Rani O Whiddett
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane 4072, QLD, Australia
| | - Danielle J Borg
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane 4072, QLD, Australia.,Faculty of Medicine, University of Queensland, Brisbane 4067, QLD, Australia
| | - Victoria C Cogger
- Charles Perkins Centre, University of Sydney, Sydney 2006, NSW, Australia.,Centre for Education and Research on Aging, and Aging and Alzheimer's Institute, Concord Hospital, Sydney 2139, NSW, Australia.,ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney 2139, NSW, Australia
| | - William O Ballard
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney 2052, NSW, Australia
| | - Nigel Turner
- Department of Pharmacology, School of Medical Sciences, Faculty of Medicine, University of New South Wales Sydney, NSW 2052, Australia
| | - Richard G Melvin
- Department of Biomedical Sciences, University of Minnesota Medical School, 1035 University Drive, Duluth 55812, MN, USA
| | - David Raubenheimer
- Charles Perkins Centre, University of Sydney, Sydney 2006, NSW, Australia.,School of Life and Environmental Sciences, University of Sydney, NSW, Australia
| | - David G Le Couteur
- Charles Perkins Centre, University of Sydney, Sydney 2006, NSW, Australia.,Centre for Education and Research on Aging, and Aging and Alzheimer's Institute, Concord Hospital, Sydney 2139, NSW, Australia.,ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney 2139, NSW, Australia
| | - Stephen J Simpson
- Charles Perkins Centre, University of Sydney, Sydney 2006, NSW, Australia.,School of Life and Environmental Sciences, University of Sydney, NSW, Australia
| | - Josephine M Forbes
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane 4072, QLD, Australia.,Faculty of Medicine, University of Queensland, Brisbane 4067, QLD, Australia.,Department of Medicine, University of Melbourne, Heidelberg, VIC 3084, Australia
| |
Collapse
|
|
36
|
Ito K, Yokoyama K, Nakayama M, Fukagawa M, Hirakata H. Association of fibroblast growth factor 23 and α-klotho in hemodialysis patients during administration of ferric citrate hydrate: post hoc analysis of ASTRIO study. BMC Nephrol 2021; 22:374. [PMID: 34758731 PMCID: PMC8582217 DOI: 10.1186/s12882-021-02575-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 10/25/2021] [Indexed: 12/28/2022] Open
Abstract
Background Fibroblast growth factor-23 (FGF23) and α-klotho are associated with anemia in patients with chronic kidney disease. In this post hoc analysis of the ASTRIO study (UMIN000019176), we investigated the relationship between FGF23 and α-klotho during treatment with an iron-based phosphate binder, ferric citrate hydrate (FC), compared with non-iron-based phosphate binders in hemodialysis (HD) patients. We examined the effect of iron absorption by FC on the relationship between FGF23 and α-klotho. There have been few clinical studies evaluating these biomarkers simultaneously in HD patients. Methods The ASTRIO study was a 24-week, randomized, open-label, multicenter trial. HD patients taking non-iron-based phosphate binder(s) were randomized at a 1:1 ratio to continue other binder(s) (control group) or switch to FC (FC group). Serum phosphate (P) and hemoglobin (Hb) were maintained within 3.5–6.0 mg/dL and 10–12 g/dL, respectively. Plasma levels of intact FGF23 (i-FGF23), C-terminal FGF23 (c-FGF23), and α-klotho were measured, as were iron-related parameters. Association analyses of FGF23 and α-klotho were conducted. Results Patients were randomized to FC (n = 48) and control (n = 45) groups. Serum ferritin significantly increased from baseline to end-of-treatment (EOT) in the FC group, compared with the control group (adjusted mean difference [95% confidence interval]: 79.5 [44.7, 114.4] ng/mL; p < 0.001). The mean change from baseline to EOT in c-FGF23 was significantly different between the FC and control groups (mean ± standard deviation (SD): − 0.2 ± 0.8 loge pg/mL vs. 0.2 ± 0.8 loge pg/mL, respectively; p = 0.04). The mean change from baseline to EOT in i-FGF23 and α-klotho were not significantly different between the FC and control groups (mean ± SD: − 0.1 ± 0.8 loge pg/mL vs. 0.1 ± 0.9 loge pg/mL; p = 0.33, and 2.0 ± 91.5 pg/mL vs. − 8.9 ± 145.3; p = 0.58, respectively). However, both forms of FGF23 and α-klotho were not significantly associated with each other in both groups. Conclusions Iron absorbed via FC administration in HD patients did not influence the correlation relationship between plasma levels of FGF23 and α-klotho under the condition of serum P and Hb were maintained. Trial registration ASTRIO study (UMIN000019176, registered at UMIN Clinical Trials Registry on October 1, 2015).
Collapse
Affiliation(s)
- Kyoko Ito
- Medical Affairs Department, Torii Pharmaceutical Co. Ltd., Tokyo, Japan
| | - Keitaro Yokoyama
- Health Care Center, Harumi Toriton Clinic, The Jikei University Hospital, 1-8-8 Harumi, Chuo-ku, Tokyo, 104-0053, Japan.
| | - Masaaki Nakayama
- St. Luke's International University, St. Luke's International Hospital, Tokyo, Japan
| | - Masafumi Fukagawa
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan
| | | |
Collapse
|
|
37
|
Zhou H, Pu S, Zhou H, Guo Y. Klotho as Potential Autophagy Regulator and Therapeutic Target. Front Pharmacol 2021; 12:755366. [PMID: 34737707 PMCID: PMC8560683 DOI: 10.3389/fphar.2021.755366] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 10/07/2021] [Indexed: 12/22/2022] Open
Abstract
The protein Klotho can significantly delay aging, so it has attracted widespread attention. Abnormal downregulation of Klotho has been detected in several aging-related diseases, such as Alzheimer’s disease, kidney injury, cancer, chronic obstructive pulmonary disease (COPD), vascular disease, muscular dystrophy and diabetes. Conversely, many exogenous and endogenous factors, several drugs, lifestyle changes and genetic manipulations were reported to exert therapeutic effects through increasing Klotho expression. In recent years, Klotho has been identified as a potential autophagy regulator. How Klotho may contribute to reversing the effects of aging and disease became clearer when it was linked to autophagy, the process in which eukaryotic cells clear away dysfunctional proteins and damaged organelles: the abovementioned diseases involve abnormal autophagy. Interestingly, growing evidence indicates that Klotho plays a dual role as inducer or inhibitor of autophagy in different physiological or pathological conditions through its influence on IGF-1/PI3K/Akt/mTOR signaling pathway, Beclin 1 expression and activity, as well as aldosterone level, which can help restore autophagy to beneficial levels. The present review examines the role of Klotho in regulating autophagy in Alzheimer’s disease, kidney injury, cancer, COPD, vascular disease, muscular dystrophy and diabetes. Targeting Klotho may provide a new perspective for preventing and treating aging-related diseases.
Collapse
Affiliation(s)
- Hongjing Zhou
- Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shiyun Pu
- Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Houfeng Zhou
- Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuanxin Guo
- Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| |
Collapse
|
|
38
|
Gembillo G, Visconti L, Giusti MA, Siligato R, Gallo A, Santoro D, Mattina A. Cardiorenal Syndrome: New Pathways and Novel Biomarkers. Biomolecules 2021; 11:1581. [PMID: 34827580 PMCID: PMC8615764 DOI: 10.3390/biom11111581] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/22/2021] [Accepted: 10/22/2021] [Indexed: 12/15/2022] Open
Abstract
Cardiorenal syndrome (CRS) is a multi-organ disease characterized by the complex interaction between heart and kidney during acute or chronic injury. The pathogenesis of CRS involves metabolic, hemodynamic, neurohormonal, and inflammatory mechanisms, and atherosclerotic degeneration. In the process of better understanding the bi-directional pathophysiological aspects of CRS, the need to find precise and easy-to-use markers has also evolved. Based on the new pathophysiological standpoints and an overall vision of the CRS, the literature on renal, cardiac, metabolic, oxidative, and vascular circulating biomarkers was evaluated. Though the effectiveness of different extensively applied biomarkers remains controversial, evidence for several indicators, particularly when combined, has increased in recent years. From new aspects of classic biomarkers to microRNAs, this review aimed at a 360-degree analysis of the pathways that balance the kidney and the heart physiologies. In this delicate system, different markers and their combination can shed light on the diagnosis, risk, and prognosis of CRS.
Collapse
Affiliation(s)
- Guido Gembillo
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy;
- Department of Biomedical and Dental Sciences and Morpho-Functional Imaging, University of Messina, 98125 Messina, Italy
| | - Luca Visconti
- Unit of Nephrology and Dialysis, Ospedali Riuniti Villa Sofia Cervello, University of Palermo, 90146 Palermo, Italy;
| | - Maria Ausilia Giusti
- Diabetes and Islet Transplantation Unit, Department of Diagnostic and Therapeutic Services, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), UPMC Italy, 90127 Palermo, Italy; (M.A.G.); (A.M.)
| | - Rossella Siligato
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy;
- Department of Biomedical and Dental Sciences and Morpho-Functional Imaging, University of Messina, 98125 Messina, Italy
| | - Alessia Gallo
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), UPMC Italy, 90127 Palermo, Italy;
| | - Domenico Santoro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy;
| | - Alessandro Mattina
- Diabetes and Islet Transplantation Unit, Department of Diagnostic and Therapeutic Services, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), UPMC Italy, 90127 Palermo, Italy; (M.A.G.); (A.M.)
| |
Collapse
|
|
39
|
Ammar Y, Mohamed A, Khalil G, Maharem D. Accelerated Atherosclerosis in Systemic Lupus Erythematosus: Role of Fibroblast Growth Factor 23- Phosphate Axis. Int J Nephrol Renovasc Dis 2021; 14:331-347. [PMID: 34475774 PMCID: PMC8407679 DOI: 10.2147/ijnrd.s326399] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 08/05/2021] [Indexed: 01/16/2023] Open
Abstract
PURPOSE Despite management advances, accelerated atherosclerotic cardiovascular disease (ACVD) remains a major cause of morbimortality in systemic lupus erythematosus (SLE) patients; that is not fully explained by traditional risk factors. Fibroblast growth factor-23 (FGF23) is a bone-derived phosphaturic hormone with multiple klotho-dependent and independent effects, including promotion of atherosclerosis and vascular calcification, particularly in the context of chronic kidney disease. Increased circulating FGF23 was reported in SLE patients, particularly with lupus nephritis (LN); but its atherogenic role in these disorders was not explored. SUBJECTS AND METHODS Three study groups of predominantly middle-aged females were categorized by the 2012 SLE International Collaborating Clinics (SLICC) criteria as SLE (without LN), LN, or controls matching for traditional CVD risk profile. Measures of SLE activity, damage, steroid therapy, and glomerular filtration rate were calculated. Fasting blood samples were checked for serum lipid profile, anti-DNA, urea, creatinine, uric acid, proteins, albumin, calcium, phosphorus, C3, C4, CRP, vitamin-D3, intact parathyroid hormone and FGF23 (iFGF23). By carotid ultrasonography, mean common carotid artery intima-media thickness (CC-IMT), plaque score (PS) and internal carotid resistive index (ICRI) were recorded. RESULTS CC-IMT, ICRI and serum iFGF23 differed along the study groups (LN>SLE>controls). In both SLE and LN patients, serum iFGF23 had a significant positive correlation with serum phosphorus, CC-IMT and PS. On multivariate analysis, the strongest predictor of increased CC-IMT was cumulative steroid dose in SLE and serum iFGF23 in LN patients. Most significant independent predictors of increased serum iFGF23 were hyperphosphatemia in SLE and proteinuria in LN patients. CONCLUSION FGF23-phosphate axis has a key role in accelerated ACVD in SLE patients. Serum phosphorus and iFGF23 should be included in ACVD risk profile assessment of these patients. Prospective studies shall define the role of dietary and/or pharmacologic control of hyperphosphatemia and proteinuria in reducing circulating iFGF23 and ACVD in them.
Collapse
Affiliation(s)
- Yaser Ammar
- Internal Medicine Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Amira Mohamed
- Internal Medicine Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Gihane Khalil
- Chemical Pathology Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Dalia Maharem
- Internal Medicine Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
| |
Collapse
|
|
40
|
Negative regulators of TGF-β1 signaling in renal fibrosis; pathological mechanisms and novel therapeutic opportunities. Clin Sci (Lond) 2021; 135:275-303. [PMID: 33480423 DOI: 10.1042/cs20201213] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 12/23/2020] [Accepted: 01/08/2021] [Indexed: 02/06/2023]
Abstract
Elevated expression of the multifunctional cytokine transforming growth factor β1 (TGF-β1) is causatively linked to kidney fibrosis progression initiated by diabetic, hypertensive, obstructive, ischemic and toxin-induced injury. Therapeutically relevant approaches to directly target the TGF-β1 pathway (e.g., neutralizing antibodies against TGF-β1), however, remain elusive in humans. TGF-β1 signaling is subjected to extensive negative control at the level of TGF-β1 receptor, SMAD2/3 activation, complex assembly and promoter engagement due to its critical role in tissue homeostasis and numerous pathologies. Progressive kidney injury is accompanied by the deregulation (loss or gain of expression) of several negative regulators of the TGF-β1 signaling cascade by mechanisms involving protein and mRNA stability or epigenetic silencing, further amplifying TGF-β1/SMAD3 signaling and fibrosis. Expression of bone morphogenetic proteins 6 and 7 (BMP6/7), SMAD7, Sloan-Kettering Institute proto-oncogene (Ski) and Ski-related novel gene (SnoN), phosphate tensin homolog on chromosome 10 (PTEN), protein phosphatase magnesium/manganese dependent 1A (PPM1A) and Klotho are dramatically decreased in various nephropathies in animals and humans albeit with different kinetics while the expression of Smurf1/2 E3 ligases are increased. Such deregulations frequently initiate maladaptive renal repair including renal epithelial cell dedifferentiation and growth arrest, fibrotic factor (connective tissue growth factor (CTGF/CCN2), plasminogen activator inhibitor type-1 (PAI-1), TGF-β1) synthesis/secretion, fibroproliferative responses and inflammation. This review addresses how loss of these negative regulators of TGF-β1 pathway exacerbates renal lesion formation and discusses the therapeutic value in restoring the expression of these molecules in ameliorating fibrosis, thus, presenting novel approaches to suppress TGF-β1 hyperactivation during chronic kidney disease (CKD) progression.
Collapse
|
|
41
|
The Protein-Independent Role of Phosphate in the Progression of Chronic Kidney Disease. Toxins (Basel) 2021; 13:toxins13070503. [PMID: 34357974 PMCID: PMC8310030 DOI: 10.3390/toxins13070503] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 07/13/2021] [Accepted: 07/14/2021] [Indexed: 12/14/2022] Open
Abstract
Several factors contribute to renal-function decline in CKD patients, and the role of phosphate content in the diet is still a matter of debate. This study aims to analyze the mechanism by which phosphate, independent of protein, is associated with the progression of CKD. Adult Munich-Wistar rats were submitted to 5/6 nephrectomy (Nx), fed with a low-protein diet, and divided into two groups. Only phosphate content (low phosphate, LoP, 0.2%; high phosphate, HiP, 0.95%) differentiated diets. After sixty days, biochemical parameters and kidney histology were analyzed. The HiP group presented worse renal function, with higher levels of PTH, FGF-23, and fractional excretion of phosphate. In the histological analysis of the kidney tissue, they also showed a higher percentage of interstitial fibrosis, expression of α-actin, PCNA, and renal infiltration by macrophages. The LoP group presented higher expression of beclin-1 in renal tubule cells, a marker of autophagic flux, when compared to the HiP group. Our findings highlight the action of phosphate in the induction of kidney interstitial inflammation and fibrosis, contributing to the progression of renal disease. A possible effect of phosphate on the dysregulation of the renal cell autophagy mechanism needs further investigation with clinical studies.
Collapse
|
|
42
|
Trade‐offs between male fertility reduction and selected growth factors or the klotho response in a lipopolysaccharide-dependent mouse model. Toxicol Res 2021; 38:175-186. [PMID: 35415080 PMCID: PMC8960506 DOI: 10.1007/s43188-021-00098-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 04/01/2021] [Accepted: 04/20/2021] [Indexed: 11/06/2022] Open
Abstract
The increasing number of depression cases leads to a greater need for new antidepressant treatment development. It is postulated that antidepressants may harm male fertility, but the cellular mechanism is still poorly understood. The role of growth factors and klotho protein in maintaining normal male reproductive function is well documented. Hence, the study aimed to investigate the effect of the antidepressant drug – imipramine (tricyclic AD), and other substances with antidepressant potential (ALS), administered in combination or in combination with LPS (an animal model of depression) on gene expression and protein synthesis of IGF-2 (insulin-like growth factor 2), TGF-β1 (transforming growth factor β1), NGF (nerve growth factor), KGF (keratinocyte growth factor) and protein synthesis of VEGF-A (vascular endothelial growth factor A), IGF-IR (insulin-like growth factor receptor 1), EGFR (epidermal growth factor receptor) and klotho in the testis of mice. Mice were injected intraperitoneally with selected ALS and LPS or 10% DMSO (controls) (n = 7/group) once a day for 14 days. Animals were decapitated and testes collected for RNA and protein purification. PCR and western blot methods were employed for the evaluation of growth factors and klotho expression. The results obtained indicated a decreased level of most of the analyzed genes and proteins, except KGF; its expression increased after treatment with MTEP and IMI administrated individually and after NS-398, and IMI in combination with LPS. Our results may suggest that the tested ALS and LPS can contribute to a reduction of male fertility, but NS-398, IMI, and IMI+NS-398 may also act as stimulants after LPS.
Collapse
|
|
43
|
Tsuchiya K, Akihisa T. The Importance of Phosphate Control in Chronic Kidney Disease. Nutrients 2021; 13:nu13051670. [PMID: 34069053 PMCID: PMC8156430 DOI: 10.3390/nu13051670] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/06/2021] [Accepted: 05/12/2021] [Indexed: 12/12/2022] Open
Abstract
A series of problems including osteopathy, abnormal serum data, and vascular calcification associated with chronic kidney disease (CKD) are now collectively called CKD-mineral bone disease (CKD-MBD). The pathophysiology of CKD-MBD is becoming clear with the emerging of αKlotho, originally identified as a progeria-causing protein, and bone-derived phosphaturic fibroblast growth factor 23 (FGF23) as associated factors. Meanwhile, compared with calcium and parathyroid hormone, which have long been linked with CKD-MBD, phosphate is now attracting more attention because of its association with complications and outcomes. Incidentally, as the pivotal roles of FGF23 and αKlotho in phosphate metabolism have been unveiled, how phosphate metabolism and hyperphosphatemia are involved in CKD-MBD and how they can be clinically treated have become of great interest. Thus, the aim of this review is reconsider CKD-MBD from the viewpoint of phosphorus, its involvement in the pathophysiology, causing complications, therapeutic approach based on the clinical evidence, and clarifying the importance of phosphorus management.
Collapse
Affiliation(s)
- Ken Tsuchiya
- Department of Blood Purification, Tokyo Women’s Medical University, Tokyo 162-8666, Japan
- Correspondence:
| | - Taro Akihisa
- Department of Nephrology, Tokyo Women’s Medical University, Tokyo 162-8666, Japan;
| |
Collapse
|
|
44
|
Tippen SP, Noonan ML, Ni P, Metzger CE, Swallow EA, Sacks SA, Chen NX, Thompson WR, Prideaux M, Atkins GJ, Moe SM, Allen MR, White KE. Age and sex effects on FGF23-mediated response to mild phosphate challenge. Bone 2021; 146:115885. [PMID: 33618073 PMCID: PMC8009839 DOI: 10.1016/j.bone.2021.115885] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/07/2021] [Accepted: 02/09/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND During aging, there is a normal and mild loss in kidney function that leads to abnormalities of the kidney-bone metabolic axis. In the setting of increased phosphorus intake, hyperphosphatemia can occur despite increased concentrations of the phosphaturic hormone FGF23. This is likely from decreased expression of the FGF23 co-receptor Klotho (KL) with age; however, the roles of age and sex in the homeostatic responses to mild phosphate challenges remain unclear. METHODS Male and female 16-week and 78-week mice were placed on either normal grain-based chow or casein (higher bioavailable phosphate) diets for 8 weeks. Gene expression, serum biochemistries, micro-computed tomography, and skeletal mechanics were used to assess the impact of mild phosphate challenge on multiple organ systems. Cell culture of differentiated osteoblast/osteocytes was used to test mechanisms driving key outcomes. RESULTS Aging female mice responded to phosphate challenge by significantly elevating serum intact FGF23 (iFGF23) versus control diet; males did not show this response. Male mice, regardless of age, exhibited higher kidney KL mRNA with similar phosphate levels across both sexes. However, males and females had similar blood phosphate, calcium, and creatinine levels irrespective of age, suggesting that female mice upregulated FGF23 to maintain blood phosphorus, and compromised renal function could not explain the increased serum iFGF23. The 17β-estradiol levels were not different between groups, and in vivo bone steroid receptor (estrogen receptor 1 [Esr1], estrogen receptor 2 [Esr2], androgen receptor [Ar]) expression was not different by age, sex, or diet. Trabecular bone volume was higher in males but decreased with both age and phosphate challenge in both sexes. Cortical porosity increased with age in males but not females. In vitro studies demonstrated that 17β-estradiol treatment upregulated FGF23 and Esr2 mRNAs in a dose-dependent manner. CONCLUSIONS Our study demonstrates that aging female mice upregulate FGF23 to a greater degree during a mild phosphate challenge to maintain blood phosphorus versus young female and young/old male mice, potentially due to direct estradiol effects on osteocytes. Thus, the control of phosphate intake during aging could have modifiable outcomes for FGF23-related phenotypes.
Collapse
Affiliation(s)
- Samantha P Tippen
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Megan L Noonan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Pu Ni
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Corinne E Metzger
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Elizabeth A Swallow
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Spencer A Sacks
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Neal X Chen
- Medicine/Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - William R Thompson
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Physical Therapy, Indiana University School of Health and Human Sciences, Indianapolis, IN 46202, USA
| | - Matthew Prideaux
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Gerald J Atkins
- Centre for Orthopaedic and Trauma Research, The University of Adelaide, Adelaide, SA 5000, Australia
| | - Sharon M Moe
- Medicine/Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Matthew R Allen
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Medicine/Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Roudebush Veterans Administration Medical Center, Indianapolis, IN 46202, USA
| | - Kenneth E White
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Medicine/Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| |
Collapse
|
|
45
|
Uremic Toxins in the Progression of Chronic Kidney Disease and Cardiovascular Disease: Mechanisms and Therapeutic Targets. Toxins (Basel) 2021; 13:toxins13020142. [PMID: 33668632 PMCID: PMC7917723 DOI: 10.3390/toxins13020142] [Citation(s) in RCA: 158] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 02/08/2021] [Accepted: 02/10/2021] [Indexed: 12/24/2022] Open
Abstract
Chronic kidney disease (CKD) is a progressive loss of renal function. The gradual decline in kidney function leads to an accumulation of toxins normally cleared by the kidneys, resulting in uremia. Uremic toxins are classified into three categories: free water-soluble low-molecular-weight solutes, protein-bound solutes, and middle molecules. CKD patients have increased risk of developing cardiovascular disease (CVD), due to an assortment of CKD-specific risk factors. The accumulation of uremic toxins in the circulation and in tissues is associated with the progression of CKD and its co-morbidities, including CVD. Although numerous uremic toxins have been identified to date and many of them are believed to play a role in the progression of CKD and CVD, very few toxins have been extensively studied. The pathophysiological mechanisms of uremic toxins must be investigated further for a better understanding of their roles in disease progression and to develop therapeutic interventions against uremic toxicity. This review discusses the renal and cardiovascular toxicity of uremic toxins indoxyl sulfate, p-cresyl sulfate, hippuric acid, TMAO, ADMA, TNF-α, and IL-6. A focus is also placed on potential therapeutic targets against uremic toxicity.
Collapse
|
|
46
|
Ewendt F, Feger M, Föller M. Role of Fibroblast Growth Factor 23 (FGF23) and αKlotho in Cancer. Front Cell Dev Biol 2021; 8:601006. [PMID: 33520985 PMCID: PMC7841205 DOI: 10.3389/fcell.2020.601006] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 10/15/2020] [Indexed: 12/16/2022] Open
Abstract
Together with fibroblast growth factors (FGFs) 19 and 21, FGF23 is an endocrine member of the family of FGFs. Mainly secreted by bone cells, FGF23 acts as a hormone on the kidney, stimulating phosphate excretion and suppressing formation of 1,25(OH)2D3, active vitamin D. These effects are dependent on transmembrane protein αKlotho, which enhances the binding affinity of FGF23 for FGF receptors (FGFR). Locally produced FGF23 in other tissues including liver or heart exerts further paracrine effects without involvement of αKlotho. Soluble Klotho (sKL) is an endocrine factor that is cleaved off of transmembrane Klotho or generated by alternative splicing and regulates membrane channels, transporters, and intracellular signaling including insulin growth factor 1 (IGF-1) and Wnt pathways, signaling cascades highly relevant for tumor progression. In mice, lack of FGF23 or αKlotho results in derangement of phosphate metabolism and a syndrome of rapid aging with abnormalities affecting most organs and a very short life span. Conversely, overexpression of anti-aging factor αKlotho results in a profound elongation of life span. Accumulating evidence suggests a major role of αKlotho as a tumor suppressor, at least in part by inhibiting IGF-1 and Wnt/β-catenin signaling. Hence, in many malignancies, higher αKlotho expression or activity is associated with a more favorable outcome. Moreover, also FGF23 and phosphate have been revealed to be factors relevant in cancer. FGF23 is particularly significant for those forms of cancer primarily affecting bone (e.g., multiple myeloma) or characterized by bone metastasis. This review summarizes the current knowledge of the significance of FGF23 and αKlotho for tumor cell signaling, biology, and clinically relevant parameters in different forms of cancer.
Collapse
Affiliation(s)
- Franz Ewendt
- Department of Nutritional Physiology, Institute of Agricultural and Nutritional Sciences, Martin-Luther University Halle-Wittenberg, Halle, Germany
| | - Martina Feger
- Department of Physiology, University of Hohenheim, Stuttgart, Germany
| | - Michael Föller
- Department of Physiology, University of Hohenheim, Stuttgart, Germany
| |
Collapse
|
|
47
|
Pasaoglu OT, Senelmis A, Helvaci O, Derici U, Pasaoglu H. FGF23, alpha-Klotho and vitamin D mediated calcium-phosphate metabolism in haemodialysis patients. J Med Biochem 2021; 40:160-166. [PMID: 33776565 PMCID: PMC7982292 DOI: 10.5937/jomb0-27408] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 08/26/2020] [Indexed: 11/16/2022] Open
Abstract
Background Klotho is a prote˝in that acts as a co-receptor for FGF23. FGF23-Klotho axis has great importance regarding the regulation of mineral metabolism by kidneys. In this study, we analysed FGF23, Klotho, 1,25-dihydroxyvitamin D3, 25-hydroxyvitamin D, parathormone, Calcium and Phosphate levels of haemodialysis patients in order to investigate the nature of the mineral metabolism disruption in chronic kidney diseases. Methods Sixty haemodialysis patients and 34 healthy controls were included in the study. Serum iFGF, cFGF, and soluble Klotho were analysed using ELISA kits. Moreover, 1,25-dihydroxyvitamin D3 was determined using LCMS/MS. Calcium, phosphate, iPTH and 25-hydroxyvitamin D were measured using autoanalyzers. Results In haemodialysis patients, iFGF23, cFGF23, iPTH and P levels were significantly higher, and 1,25-dihydroxyvitamin D3, Klotho and Ca levels were significantly lower compared with the control group. There was no significant difference in the 25-hydroxyvitamin D levels. Conclusions Our study showed that lack of sufficient amounts of Klotho is crucial for mineral metabolism disruptions seen as a complication of chronic kidney diseases. Despite the high levels of the hormone, FGF23 is unable to accomplish its function properly, likely due to deteriorated kidney function in haemodialysis patients.
Collapse
Affiliation(s)
- Ozge Tugce Pasaoglu
- Gazi University, Faculty of Health Sciences, Department of Nutrition and Dietetics, Ankara, Turkey
| | - Ayse Senelmis
- Gazi University, Faculty of Medicine, Department of Medical Biochemistry, Ankara, Turkey
| | - Ozant Helvaci
- Gazi University, Faculty of Medicine, Department of Internal Medicine, Section of Nephrology, Ankara, Turkey
| | - Ulver Derici
- Gazi University, Faculty of Medicine, Department of Internal Medicine, Section of Nephrology, Ankara, Turkey
| | - Hatice Pasaoglu
- Gazi University, Faculty of Medicine, Department of Medical Biochemistry, Ankara, Turkey
| |
Collapse
|
|
48
|
Neyra JA, Hu MC, Moe OW. Klotho in Clinical Nephrology: Diagnostic and Therapeutic Implications. Clin J Am Soc Nephrol 2020; 16:162-176. [PMID: 32699047 PMCID: PMC7792642 DOI: 10.2215/cjn.02840320] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
αKlotho (called Klotho here) is a membrane protein that serves as the coreceptor for the circulating hormone fibroblast growth factor 23 (FGF23). Klotho is also cleaved and released as a circulating substance originating primarily from the kidney and exerts a myriad of housekeeping functions in just about every organ. The vital role of Klotho is shown by the multiorgan failure with genetic deletion in rodents, with certain features reminiscent of human disease. The most common causes of systemic Klotho deficiency are AKI and CKD. Preclinical data on Klotho biology have advanced considerably and demonstrated its potential diagnostic and therapeutic value; however, multiple knowledge gaps exist in the regulation of Klotho expression, release, and metabolism; its target organs; and mechanisms of action. In the translational and clinical fronts, progress has been more modest. Nonetheless, Klotho has potential clinical applications in the diagnosis of AKI and CKD, in prognosis of progression and extrarenal complications, and finally, as replacement therapy for systemic Klotho deficiency. The overall effect of Klotho in clinical nephrology requires further technical advances and additional large prospective human studies.
Collapse
Affiliation(s)
- Javier A. Neyra
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, Dallas, Texas
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Division of Nephrology, Bone and Mineral Metabolism, Department of Internal Medicine, University of Kentucky, Lexington, Kentucky
| | - Ming Chang Hu
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, Dallas, Texas
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Orson W. Moe
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, Dallas, Texas
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas
| |
Collapse
|
|
49
|
Xu J, Zhou L, Liu Y. Cellular Senescence in Kidney Fibrosis: Pathologic Significance and Therapeutic Strategies. Front Pharmacol 2020; 11:601325. [PMID: 33362554 PMCID: PMC7759549 DOI: 10.3389/fphar.2020.601325] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 10/21/2020] [Indexed: 01/10/2023] Open
Abstract
Age-related disorders such as chronic kidney disease (CKD) are increasingly prevalent globally and pose unprecedented challenges. In many aspects, CKD can be viewed as a state of accelerated and premature aging. Aging kidney and CKD share many common characteristic features with increased cellular senescence, a conserved program characterized by an irreversible cell cycle arrest with altered transcriptome and secretome. While developmental senescence and acute senescence may positively contribute to the fine-tuning of embryogenesis and injury repair, chronic senescence, when unresolved promptly, plays a crucial role in kidney fibrogenesis and CKD progression. Senescent cells elicit their fibrogenic actions primarily by secreting an assortment of inflammatory and profibrotic factors known as the senescence-associated secretory phenotype (SASP). Increasing evidence indicates that senescent cells could be a promising new target for therapeutic intervention known as senotherapy, which includes depleting senescent cells, modulating SASP and restoration of senescence inhibitors. In this review, we discuss current understanding of the role and mechanism of cellular senescence in kidney fibrosis. We also highlight potential options of targeting senescent cells for the treatment of CKD.
Collapse
Affiliation(s)
- Jie Xu
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lili Zhou
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Youhua Liu
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| |
Collapse
|
|
50
|
Solache-Berrocal G, Rolle-Sóñora V, Martín-Fernández N, Cambray S, Valdivielso JM, Rodríguez I. CYP24A1 and KL polymorphisms are associated with the extent of vascular calcification but do not improve prediction of cardiovascular events. Nephrol Dial Transplant 2020; 36:2076-2083. [PMID: 33219692 PMCID: PMC8577629 DOI: 10.1093/ndt/gfaa240] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Indexed: 11/25/2022] Open
Abstract
Background Novel ways of determining cardiovascular risk are needed as a consequence of population ageing and the increased prevalence of chronic kidney disease (CKD), both of which favour vascular calcification. Since the formation of arterial calcium deposits has a genetic component, single nucleotide polymorphisms (SNPs) could predict cardiovascular events. Methods A selection of 1927 CKD patients and controls recruited by the NEFRONA study were genotyped for 60 SNPs from 22 candidate genes. A calcium score was calculated from the echogenicity of arterial atherosclerotic plaques and the presence of cardiovascular events during a 4-year period was recorded. Association of SNPs with the calcium score was identified by multiple linear regression models and their capacity to predict events was assessed by means of Cox proportional hazards regression and receiver operating characteristics curves. Results Two variants, rs2296241 of CYP24A1 and rs495392 of KL, were associated with the calcium score. Despite this, only heterozygotes for rs495392 had a lower risk of suffering an event compared with homozygotes for the major allele {hazard ratio (HR) 0.67 [95% confidence interval (CI) 0.48−0.93]}. Of note, the calcium score was associated with an increased risk of cardiovascular events [HR 1.71 (95% CI 1.35−2.17)]. The addition of the rs495392 genotype to classical cardiovascular risk factors did not increase the predictive power [area under the curve (AUC) 71.3 (95% CI 61.1−85.5) versus 71.4 (61.5−81.4)]. Conclusions Polymorphisms of CYP24A1 and KL are associated with the extent of calcification but do not predict cardiovascular events. However, the echogenic determination of the extent of calcium deposits seems a promising non-irradiating method for the scoring of calcification in high-risk populations.
Collapse
Affiliation(s)
- Guillermo Solache-Berrocal
- Cardiac Pathology Research Group, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.,Renal Research Network (REDinREN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Valeria Rolle-Sóñora
- Biostatistics and Epidemiology Platform, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | | | - Serafí Cambray
- Vascular and Renal Translational Research Group, Biomedical Research Institute IRBLleida, Lleida, Spain
| | - José Manuel Valdivielso
- Renal Research Network (REDinREN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.,Vascular and Renal Translational Research Group, Biomedical Research Institute IRBLleida, Lleida, Spain
| | - Isabel Rodríguez
- Cardiac Pathology Research Group, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.,Renal Research Network (REDinREN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| |
Collapse
|