|
1
|
Srinivasan S, Ramos-Lewis W, Morais MRPT, Chi Q, Soh AWJ, Williams E, Lennon R, Sherwood DR. A collagen IV fluorophore knock-in toolkit reveals trimer diversity in C. elegans basement membranes. J Cell Biol 2025; 224:e202412118. [PMID: 40100062 PMCID: PMC11917169 DOI: 10.1083/jcb.202412118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Revised: 02/20/2025] [Accepted: 02/28/2025] [Indexed: 03/20/2025] Open
Abstract
The type IV collagen triple helix, composed of three ⍺-chains, is a core basement membrane (BM) component that assembles into a network within BMs. Endogenous tagging of all ⍺-chains with genetically encoded fluorophores has remained elusive, limiting our understanding of this crucial BM component. Through genome editing, we show that the C termini of the C. elegans type IV collagen ⍺-chains EMB-9 and LET-2 can be fused to a variety of fluorophores to create a strain toolkit with wild-type health. Using quantitative imaging, our results suggest a preference for LET-2-LET-2-EMB-9 trimer construction, but also tissue-specific flexibility in trimers assembled driven by differences in ⍺-chain expression levels. By tagging emb-9 and let-2 mutants that model human Gould syndrome, a complex multitissue disorder, we further discover defects in extracellular accumulation and turnover that might help explain disease pathology. Together, our findings identify a permissive tagging site in C. elegans that will allow diverse studies on type IV collagen regulation and function in animals.
Collapse
Affiliation(s)
| | | | - Mychel R P T Morais
- Division of Cell-Matrix Biology and Regenerative Medicine, Wellcome Centre for Cell-Matrix Research, School of Biological Sciences, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
| | - Qiuyi Chi
- Department of Biology, Duke University, Durham, NC, USA
| | - Adam W J Soh
- Department of Biology, Duke University, Durham, NC, USA
| | - Emily Williams
- Division of Cell-Matrix Biology and Regenerative Medicine, Wellcome Centre for Cell-Matrix Research, School of Biological Sciences, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
| | - Rachel Lennon
- Division of Cell-Matrix Biology and Regenerative Medicine, Wellcome Centre for Cell-Matrix Research, School of Biological Sciences, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
| | | |
Collapse
|
|
2
|
Huang M, Chang J, Liu Y, Yin J, Zeng X. Apelin/APJ alleviates diabetic nephropathy by improving glomerular endothelial cells dysfunction via SIRT3‑KLF15. Mol Med Rep 2025; 31:122. [PMID: 40052569 PMCID: PMC11920778 DOI: 10.3892/mmr.2025.13487] [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: 10/17/2024] [Accepted: 01/07/2024] [Indexed: 03/21/2025] Open
Abstract
Glomerular basement membrane (GBM) thickening, the earliest morphological change of diabetic nephropathy (DN), is related to glomerular endothelial cells (GECs) dysfunction which increase extracellular matrix (ECM) synthesizing. Apelin, the endogenous ligand for apelin/apelin receptor (APJ), is reported to alleviate endothelial cell dysfunction in DN. Therefore, it was hypothesized that apelin/APJ reduced GBM thickening by decreasing the synthesis of ECM in GECs. The results showed that apelin reduced glomerular fibrosis and GBM thickening by decreasing the expression of laminin and collagen IV in diabetic mice, which were cancelled following APJ knockout in GECs. Furthermore, apelin/APJ inhibited the synthesis of laminin and collagen IV in GECs by increasing the expression and activity of SIRT3, which promoted KLF15 deacetylation and translocation into nucleus. In conclusion, apelin/APJ reduced GBM thickening in diabetes mellitus by preventing laminin and collagen IV synthesizing via SIRT3‑KLF15 pathway in GECs.
Collapse
Affiliation(s)
- Mingcong Huang
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, P.R. China
| | - Jing Chang
- Department of Physiology, Beijing You An Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Yu Liu
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, P.R. China
| | - Jiming Yin
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Xiangjun Zeng
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, P.R. China
| |
Collapse
|
|
3
|
Viggiano D, Joshi R, Borriello G, Cacciola G, Gonnella A, Gigliotti A, Nigro M, Gigliotti G. SGLT2 Inhibitors: The First Endothelial-Protector for Diabetic Nephropathy. J Clin Med 2025; 14:1241. [PMID: 40004772 PMCID: PMC11856817 DOI: 10.3390/jcm14041241] [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: 01/06/2025] [Revised: 02/05/2025] [Accepted: 02/07/2025] [Indexed: 02/27/2025] Open
Abstract
Sodium-glucose co-transporter type 2 inhibitors (SGLT2i) have emerged as a class of agents relevant for managing diabetic nephropathy and cardiopathy. In a previous report, we noticed that these drugs share, with other drugs with "nephroprotective" effects, the ability to reduce the glomerular filtration rate (GFR), thus suggesting the kidney hemodynamic effect as a proxy for optimal drug dosage. We also noticed that all known nephroprotective drugs exert cardioprotective functions, suggesting the possibility of activities not mediated by the kidney. Finally, we observe that nephroprotective drugs can be grouped according to their effects on hemoglobin levels, thus suggesting their mechanism of action. While the primary mechanism of SGLT2i involves glycosuria and natriuria, growing evidence suggests broader therapeutic effects beyond hemodynamic modulation. Specifically, the evidence that SGLT2 can be expressed in several atypical regions under pathological conditions, supports the possibility that its inhibition has several extratubular effects. Evidence supports the hypothesis that SGLT2i influence mitochondrial function in various cell types affected by diabetes, particularly in the context of diabetic nephropathy. Notably, in SGLT2i-treated patients, the extent of albumin-creatinine ratio (ACR) reduction post-treatment may be correlated with mitochondrial staining intensity in glomerular endothelial cells. This implies that the anti-proteinuric effects of SGLT2i could involve direct actions on glomerular endothelial cell. Our investigation into the role of SGLT2 inhibitors (SGLT2i) in endothelial function suggests that the aberrant expression of SGLT2 in endothelial cells in T2DM would lead to intracellular accumulation of glucose; therefore, SGLT2i are the first type of endothelial protective drugs available today, with potential implications for ageing-related kidney disease. The review reveals two major novel findings: SGLT2 inhibitors are the first known class of endothelial-protective drugs, due to their ability to prevent glucose accumulation in endothelial cells where SGLT2 is aberrantly expressed in Type 2 Diabetes. Additionally, the research demonstrates that SGLT2 inhibitors share a GFR-reducing effect with other nephroprotective drugs, suggesting both a mechanism for optimal drug dosing and potential broader applications in ageing-related kidney disease through their effects on mitochondrial function and glomerular endothelial cells.
Collapse
Affiliation(s)
- Davide Viggiano
- Department Translational Medical Sciences, University of Campania, 80138 Naples, Italy; (R.J.); (G.B.); (G.C.)
| | - Rashmi Joshi
- Department Translational Medical Sciences, University of Campania, 80138 Naples, Italy; (R.J.); (G.B.); (G.C.)
| | - Gianmarco Borriello
- Department Translational Medical Sciences, University of Campania, 80138 Naples, Italy; (R.J.); (G.B.); (G.C.)
| | - Giovanna Cacciola
- Department Translational Medical Sciences, University of Campania, 80138 Naples, Italy; (R.J.); (G.B.); (G.C.)
| | - Annalisa Gonnella
- Department Nephrology, Eboli Hospital, 84025 Eboli, Italy; (A.G.); (A.G.); (M.N.); (G.G.)
| | - Andrea Gigliotti
- Department Nephrology, Eboli Hospital, 84025 Eboli, Italy; (A.G.); (A.G.); (M.N.); (G.G.)
| | - Michelangelo Nigro
- Department Nephrology, Eboli Hospital, 84025 Eboli, Italy; (A.G.); (A.G.); (M.N.); (G.G.)
| | - Giuseppe Gigliotti
- Department Nephrology, Eboli Hospital, 84025 Eboli, Italy; (A.G.); (A.G.); (M.N.); (G.G.)
| |
Collapse
|
|
4
|
de Andrade Borges A, Ouverney G, Arruda ATS, Ribeiro AV, Ribeiro RCB, de Souza AS, da Fonseca ACC, de Queiroz LN, de Almeida ECP, Pontes B, Rabelo VWH, Ferreira V, Abreu PA, de Carvalho da Silva F, da Silva Magalhaes Forezi L, Robbs BK. Determination of Inhibitory Effect of PKM2 Enzyme and Antitumoral Activity of Novel Coumarin-naphthoquinone Hybrids. Curr Med Chem 2025; 32:359-379. [PMID: 38877863 DOI: 10.2174/0109298673298471240605072658] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 04/08/2024] [Accepted: 05/06/2024] [Indexed: 02/19/2025]
Abstract
BACKGROUND Oral squamous cell carcinoma (OSCC) represents the primary form of oral cancer, posing a significant global health threat. The existing chemotherapy options are accompanied by notable side effects impacting patient treatment adherence. Consequently, the exploration and development of novel substances with enhanced anticancer effects and fewer side effects have become pivotal in the realms of biological and chemical science. OBJECTIVE This work presents the pioneering examples of naphthoquinone-coumarin hybrids as a new category of highly effective cytotoxic substances targeting oral squamous cell carcinoma (OSCC). METHODS Given the significance of both naphthoquinones and coumarins as essential pharmacophores/ privileged structures in the quest for anticancer compounds, this study focused on the synthesis and evaluation of novel naphthoquinones/coumarin hybrids against oral squamous cell carcinoma. RESULTS By several in vitro, in silico, and in vivo approaches, we demonstrated that compound 6e was highly cytotoxic against OSCC cells and several other cancer cell types and was more selective than current chemotherapeutic drugs (carboplatin) and the naphthoquinone lapachol. Furthermore, compound 6e was non-hemolytic and tolerated in vivo at 50 mg/kg with an LD50 of 62.5 mg/kg. Furthermore, compound 6e did not induce apoptosis and cell cycle arrest but led to intracellular vesicle formation with LC3 aggregation in autophagosomes, suggesting an autophagic cell death. Additionally, 6e had a high-affinity potential for PKM2 protein, higher than the known ligands, such as lapachol or shikonin, and was able to inhibit this enzyme activity in vitro. CONCLUSION We assert that compound 6e shows promise as a potential lead for a novel chemotherapeutic drug targeting OSCC, with potential applicability to other cancer types.
Collapse
Grants
- 1A 301873/2019-4, 301873/2019-4 CNPq, Conselho Nacional de Desenvolvimento Científico e Tecnológico
- E-26/010.101106/2018, E-26/202, 787/2019, E-26/10.002250/2019, E-26/210.085/2022, E-26/010.001318/2019, E-26/211.343/2021, E-26/210.068/2021, E-26/203.191/2017-JCNE, E-26 /202.800/2017-CNE, E-26/010.101106/2018, E-26/200 .870/2021-CNE, E-26/201.369/2021-JCNE, E-26/010/ 001687/2015, E-26/202.787/2019, E-26/210.514/2019, E-26/10.002250/2019, E-26/211.343/2021, E-26/210. 085/2022, E-26/210.068/2021 FAPERJ, Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro
- 001 Coordination for the Improvement of Higher Education Personnel - Brazil (CAPES)
Collapse
Affiliation(s)
- Amanda de Andrade Borges
- Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, CEP, Niterói, 24020-141, RJ, Brazil
| | - Gabriel Ouverney
- Programa de Pós-graduação em Ciências Aplicadas a Produtos para Saúde, Faculdade de Farmácia, Universidade Federal Fluminense, CEP, Niterói, 24020-141, RJ, Brazil
| | - Afonso Thales Sousa Arruda
- Departamento de Ciência Básica, Universidade Federal Fluminense, Campus Universitário de Nova Friburgo, CEP, Nova Friburgo, 28625-650, RJ, Brazil
| | - Amanda Vieira Ribeiro
- Departamento de Ciência Básica, Universidade Federal Fluminense, Campus Universitário de Nova Friburgo, CEP, Nova Friburgo, 28625-650, RJ, Brazil
| | - Ruan Carlos Busquet Ribeiro
- Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, CEP, Niterói, 24020-141, RJ, Brazil
| | - Acacio Silva de Souza
- Departamento de Tecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Fluminense, CEP, Niterói, 24020-141, RJ, Brazil
| | - Anna Carolina Carvalho da Fonseca
- Programa de Pós-graduação em Odontologia, Instituto de Saúde de Nova Friburgo, Universidade Federal Fluminense, CEP, Nova Friburgo, 28625-650, RJ, Brazil
| | - Lucas Nicolau de Queiroz
- Programa de Pós-graduação em Ciências Aplicadas a Produtos para Saúde, Faculdade de Farmácia, Universidade Federal Fluminense, CEP, Niterói, 24020-141, RJ, Brazil
| | - Elan Cardozo Paes de Almeida
- Departamento de Ciência Básica, Universidade Federal Fluminense, Campus Universitário de Nova Friburgo, CEP, Nova Friburgo, 28625-650, RJ, Brazil
| | - Bruno Pontes
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, CEP, Rio de Janeiro, 21941-902, RJ, Brazil
| | - Vitor Won-Held Rabelo
- Instituto de Biodiversidade e Sustentabilidade, Universidade Federal do Rio de Janeiro, CEP , Macaé, 27965-045, RJ, Brazil
| | - Vitor Ferreira
- Departamento de Tecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Fluminense, CEP, Niterói, 24020-141, RJ, Brazil
| | - Paula Alvarez Abreu
- Instituto de Biodiversidade e Sustentabilidade, Universidade Federal do Rio de Janeiro, CEP , Macaé, 27965-045, RJ, Brazil
| | - Fernando de Carvalho da Silva
- Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, CEP, Niterói, 24020-141, RJ, Brazil
| | - Luana da Silva Magalhaes Forezi
- Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, CEP, Niterói, 24020-141, RJ, Brazil
| | - Bruno Kaufmann Robbs
- Departamento de Ciência Básica, Universidade Federal Fluminense, Campus Universitário de Nova Friburgo, CEP, Nova Friburgo, 28625-650, RJ, Brazil
| |
Collapse
|
|
5
|
Fatima N, Khan MI, Jawed H, Qureshi U, Ul-Haq Z, Hafizur RM, Shah TA, Dauelbait M, Bin Jardan YA, Shazly GA. Cinnamaldehyde ameliorates diabetes-induced biochemical impairments and AGEs macromolecules in a pre-clinical model of diabetic nephropathy. BMC Pharmacol Toxicol 2024; 25:85. [PMID: 39543757 PMCID: PMC11566217 DOI: 10.1186/s40360-024-00811-0] [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: 09/24/2024] [Accepted: 11/01/2024] [Indexed: 11/17/2024] Open
Abstract
PURPOSE Cinnamaldehyde, has various therapeutic potentials including glucose-lowering effect, and insulinotropic effect; however, its glycation inhibitory mechanism is not known yet. In this study, we explored the effects of cinnamaldehyde for its AGEs inhibitory mechanism in a streptozotocin-complete Freund's adjuvant (STZ-CFA) induced diabetic nephropathy (DN) rat model. METHODS Pre-clinical DN model was developed by the administration of multiple low doses of STZ-CFA in rats, mainly characterized by abnormal blood parameters and nephrotic damages. Diabetes-related systemic profile and histopathological hallmarks were evaluated using biochemical assays, microscopic imaging, immunoblot, and real-time PCR analyses, supported by cinnamaldehyde-albumin interaction assessed using STD-NMR and in silico site-directed interactions in the presence of glucose. RESULTS Cinnamaldehyde-treatment significantly reversed DN hallmarks, fasting blood glucose (FBG), serum insulin, glycated hemoglobin (HbA1c), urinary microalbumin, and creatinine contrasted to non-treated DN rats and aminoguanidine, a positive reference advanced glycation end products (AGEs) inhibitor. The pathological depositions of AGEs, receptor for advanced glycation end products (RAGE), and carboxymethyl lysine (CML), and transcriptional levels of AGE-RAGE targeted immunomodulatory factors (IL1β, TNF-α, NF-κB, TGF-β) were significantly improved in cinnamaldehyde treated rats as compared to aminoguanidine. Cinnamaldehyde post-treatment improved pancreatic pathology and systemic glycemic index (0.539 ± 0.01 vs. 0.040 ± 0.001, P < 0.001) in DN rats. Subsequently, in silico profiling of cinnamaldehyde defined the competitive binding inhibition with glucose in AGE and RAGE receptors that was further confirmed by in vitro STD-NMR analysis. CONCLUSION These findings suggest potential role of cinnamaldehyde in reversing STZ-induced diabetic nephropathic impairments; therefore, appears promising candidate for further pharmacological explorations towards diabetes-associated complications.
Collapse
Affiliation(s)
- Noor Fatima
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, 75270, Pakistan.
| | - M Israr Khan
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, 75270, Pakistan
| | - Hira Jawed
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, 75270, Pakistan
| | - Urooj Qureshi
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, 75270, Pakistan
| | - Zaheer Ul-Haq
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, 75270, Pakistan
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, 75270, Pakistan
| | - Rahman M Hafizur
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, 75270, Pakistan.
- Department of Biochemistry and Molecular Biology, Dhaka International University (DIU), Satarkul, Badda, Dhaka, 1212, Bangladesh.
- Daffodil International University, Birulia, Savar, Dhaka, 1216, Bangladesh.
| | - Tawaf Ali Shah
- College of agriculture of Agriculture Engineering and Food Science, Shandong University of Technology, Zibo, 255000, China
| | - Musaab Dauelbait
- Department of Scientific Translation, Faculty of Translation, Khartoum, 11111, Sudan.
| | - Yousef A Bin Jardan
- Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 11451, Riyadh, Saudi Arabia
| | - Gamal A Shazly
- Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 11451, Riyadh, Saudi Arabia
| |
Collapse
|
|
6
|
Ahmadpoor P, Garo F, Patrier L, Michel M, Moranne O. Anti-GBM antibody in a patient with diabetic nephropathy; all that glitters is not gold. J Nephrol 2024; 37:2357-2362. [PMID: 38805170 DOI: 10.1007/s40620-024-01926-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 02/28/2024] [Indexed: 05/29/2024]
Abstract
We present the case of a 58-year-old male diabetic patient admitted to our department for a slight decrease in kidney function, with nephrotic range proteinuria, hematuria (16,000/ml) and positive anti-glomerular basement membrane antibodies. Kidney biopsy revealed diabetic nephropathy with no evidence of crescent formation or linear immunoglobulin deposits along the basement membrane. We discuss the various clinical settings involving positive anti-glomerular basement membrane in the absence of crescentic glomerulonephritis.
Collapse
Affiliation(s)
- Pedram Ahmadpoor
- Service Néphrologie, Dialyse Aphérèse, Hôpital Universitaire de Nîmes, CHU Carémeau, Nimes, France
| | - Florian Garo
- Service Néphrologie, Dialyse Aphérèse, Hôpital Universitaire de Nîmes, CHU Carémeau, Nimes, France
- Service Anatomopathologie, Hôpital Universitaire de Nîmes, CHU Carémeau, Nimes, France
| | - Laure Patrier
- Service Néphrologie, Dialyse Aphérèse, Hôpital Universitaire de Nîmes, CHU Carémeau, Nimes, France
| | - Moise Michel
- IDESP, Université de Montpellier, Montpellier, France
- Laboratoire d'Immunologie, Hôpital Universitaire de Nîmes, CHU Carémeau, Nimes, France
| | - Olivier Moranne
- Service Néphrologie, Dialyse Aphérèse, Hôpital Universitaire de Nîmes, CHU Carémeau, Nimes, France.
- IDESP, Université de Montpellier, Montpellier, France.
| |
Collapse
|
|
7
|
Zhang Y, Musah S. Mechanosensitive Differentiation of Human iPS Cell-Derived Podocytes. Bioengineering (Basel) 2024; 11:1038. [PMID: 39451413 PMCID: PMC11504473 DOI: 10.3390/bioengineering11101038] [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: 09/14/2024] [Revised: 10/11/2024] [Accepted: 10/14/2024] [Indexed: 10/26/2024] Open
Abstract
Stem cell fate decisions, including proliferation, differentiation, morphological changes, and viability, are impacted by microenvironmental cues such as physical and biochemical signals. However, the specific impact of matrix elasticity on kidney cell development and function remains less understood due to the lack of models that can closely recapitulate human kidney biology. An established protocol to differentiate podocytes from human-induced pluripotent stem (iPS) cells provides a promising avenue to elucidate the role of matrix elasticity in kidney tissue development and lineage determination. In this study, we synthesized polyacrylamide hydrogels with different stiffnesses and investigated their ability to promote podocyte differentiation and biomolecular characteristics. We found that 3 kPa and 10 kPa hydrogels significantly support the adhesion, differentiation, and viability of podocytes. Differentiating podocytes on a more compliant (0.7 kPa) hydrogel resulted in significant cell loss and detachment. Further investigation of the mechanosensitive proteins yes-associated protein (YAP) and synaptopodin revealed nuanced molecular distinctions in cellular responses to matrix elasticity that may otherwise be overlooked if morphology and cell spreading alone were used as the primary metric for selecting matrices for podocyte differentiation. Specifically, hydrogels with kidney-like rigidities outperformed traditional tissue culture plates at modulating the molecular-level expression of active mechanosensitive proteins critical for podocyte health and function. These findings could guide the development of physiologically relevant platforms for kidney tissue engineering, disease modeling, and mechanistic studies of organ physiology and pathophysiology. Such advances are critical for realizing the full potential of in vitro platforms in accurately predicting human biological responses.
Collapse
Affiliation(s)
- Yize Zhang
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27708, USA
| | - Samira Musah
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27708, USA
- Center for Biomolecular and Tissue Engineering, Duke University, Durham, NC 27708, USA
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
- Department of Cell Biology, Duke University, Durham, NC 27710, USA
- Affiliate Faculty of the Developmental and Stem Cell Biology Program, Duke Regeneration Center, Duke MEDx Initiative, Duke University, Durham, NC 27710, USA
| |
Collapse
|
|
8
|
Zucaro L, Longobardi C, Miele A, Villanova A, Suzumoto Y. Nanocarrier-Based Drug Delivery Systems Targeting Kidney Diseases. Kidney Blood Press Res 2024; 49:884-897. [PMID: 39406192 DOI: 10.1159/000541848] [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: 08/02/2024] [Accepted: 10/04/2024] [Indexed: 11/12/2024] Open
Abstract
BACKGROUND The potential applications of nanotechnology in the medical field have become increasingly recognized in recent years. Nanocarriers have emerged as a versatile tool, offering a wide range of applications due to their unique properties. In addition to the targeted drugs delivery, nanocarriers have also proven to be extremely effective in imaging and diagnostics. Continuous advances in nanotechnology have paved the way for innovative solutions to complex challenges in human health, shaping the future of nanotechnology and its applications. SUMMARY By exploring different types of nanoparticles, this review delves into the different characteristics that can be tailored to enhance their kidney access. Although the structural complexity of the kidney may prevent nanocarriers passage, optimization of nanocarrier characteristics such as shape, size, charge, and surface modifications may overcome these barriers, allowing for targeted delivery. By harnessing the potential of nanoparticles, researchers aim to develop targeted and efficient therapies that can address various kidney-related disorders. KEY MESSAGES This review highlights the promising advancements in nanotechnology and their potential impact on improving the therapeutic outcomes for several kidney diseases.
Collapse
Affiliation(s)
- Laura Zucaro
- Biogem, Molecular Biology and Genetics Research Institute, Ariano Irpino, Italy
- Department of Mental, Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Consiglia Longobardi
- Biogem, Molecular Biology and Genetics Research Institute, Ariano Irpino, Italy
- Department of Mental, Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Antonio Miele
- Biogem, Molecular Biology and Genetics Research Institute, Ariano Irpino, Italy
- Department of Mental, Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Antonio Villanova
- Biogem, Molecular Biology and Genetics Research Institute, Ariano Irpino, Italy
- Department of Mental, Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Yoko Suzumoto
- Biogem, Molecular Biology and Genetics Research Institute, Ariano Irpino, Italy
- Institute of Biochemistry and Cell Biology, National Research Council of Italy (CNR), Naples, Italy
| |
Collapse
|
|
9
|
Salem NAB, Ismail WM, Hendawy SR, Abdelrahman AM, El-Refaey AM. Serum angiopoietin-2: a promising biomarker for early diabetic kidney disease in children and adolescents with type 1 diabetes. Eur J Pediatr 2024; 183:3853-3862. [PMID: 38884820 PMCID: PMC11322226 DOI: 10.1007/s00431-024-05637-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 05/20/2024] [Accepted: 05/30/2024] [Indexed: 06/18/2024]
Abstract
Albuminuria has been considered the golden standard biomarker for diabetic kidney disease (DKD), but appears once significant kidney damage has already occurred. Angiopoietin-2 (Angpt-2) has been implicated in the development and progression of DKD in adults. We aimed to explore the association of serum Angpt-2 levels with DKD in children and adolescents with type 1 diabetes mellitus (T1DM) of short duration (3-5 years) and to evaluate the predictive power of serum Angpt-2 in the early detection of DKD prior to the microalbuminuric phase. The current cross-sectional study included 90 children divided into three age and sex-matched groups based on urinary albumin-to-creatinine ratio (UACR): microalbuminuric diabetic group (n = 30), non-albuminuric diabetic group (n = 30), and control group (n = 30). All participants were subjected to anthropometric measurements, serum Angpt-2 and fasting lipid profile (total cholesterol, triglycerides, LDL-C, HDL-C, and Non-HDL-C) assessment. Glomerular filtration rate was estimated based on serum creatinine (eGFR-Cr). Higher serum Angpt-2 levels were detected in both diabetic groups compared to controls and in microalbuminuric compared to non-albuminuric diabetic group. There was no detected significant difference in eGFR-Cr values across the study groups. Serum Angpt-2 was positively correlated with triglycerides, LDL, Non-HDL-C, HbA1c, and UACR, while UACR, HbA1c, and Non-HDL-C were independent predictors for serum Angpt-2. Serum Angpt-2 at level of 137.4 ng/L could discriminate between microalbuminuric and non-albuminuric diabetic groups with AUC = 0.960 and at level of 115.95 ng/L could discriminate between the non-albuminuric diabetic group and controls with AUC = 0.976.Conclusion: Serum Angpt-2 is a promising potent biomarker for the detection of early stage of DKD in childhood T1DM before albuminuria emerges. What is Known? • Urine albumin-to-creatinine ratio (UACR) and glomerular filtration rate (GFR) are the golden standard but late biomarkers for DKD. • Angiopoietin-2 has been implicated in the development and progression of DKD in adults with diabetes, but has not been explored in T1DM children with DKD. What is New? • Higher serum angiopoietin-2 was detected in diabetic groups compared to controls and in microalbuminuric compared to non-albuminuric group. • Angiopoietin-2 correlated positively with triglycerides, LDL, Non-HDL-C, HbA1c, and UACR. • Serum angiopoietin-2 is a promising early diagnostic biomarker for DKD in children with T1DM.
Collapse
Affiliation(s)
- Nanees Abdel-Badie Salem
- Pediatric Endocrinology and Diabetes Unit, Department of Pediatrics, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | - Wafaa M Ismail
- Mansoura University Children's Hospital, Mansoura, Egypt
| | - Shimaa R Hendawy
- Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ashraf M Abdelrahman
- Department of Diagnostic Radiology, Mansoura University Children's Hospital, Mansoura, Egypt
| | - Ahmed M El-Refaey
- Nephrology Unit, Department of Pediatrics, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| |
Collapse
|
|
10
|
Rhode H, Tautkus B, Weigel F, Schitke J, Metzing O, Boeckhaus J, Kiess W, Gross O, Dost A, John-Kroegel U. Preclinical Detection of Early Glomerular Injury in Children with Kidney Diseases-Independently of Usual Markers of Kidney Impairment and Inflammation. Int J Mol Sci 2024; 25:9320. [PMID: 39273271 PMCID: PMC11395411 DOI: 10.3390/ijms25179320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 08/23/2024] [Accepted: 08/24/2024] [Indexed: 09/15/2024] Open
Abstract
Glomerular kidney diseases typically begin insidiously and can progress to end stage kidney failure. Early onset of therapy can slow down disease progression. Early diagnosis is required to ensure such timely therapy. The goal of our study was to evaluate protein biomarkers (BMs) for common nephropathies that have been described for children with Alport syndrome. Nineteen candidate BMs were determined by commercial ELISA in children with congenital anomalies of the kidneys and urogenital tract, inflammatory kidney injury, or diabetes mellitus. It is particularly essential to search for kidney disease BMs in children because they are a crucial target group that likely exhibits early disease stages and in which misleading diseases unrelated to the kidney are rare. Only minor differences in blood between affected individuals and controls were found. However, in urine, several biomarker candidates alone or in combination seemed to be promising indicators of renal injury in early disease stages. The BMs of highest sensitivity and specificity were collagen type XIII, hyaluronan-binding protein 2, and complement C4-binding protein. These proteins are unrelated to inflammation markers or to risk factors for and signs of renal failure. In conclusion, our study evaluated several strong candidates for screening for early stages of kidney diseases and can help to establish early nephroprotective regimens.
Collapse
Grants
- German Federal Ministry of Education and Research (01KG1104), German Research Foundation (GR1852/6-1), Thuringian Ministry for Education, Science, and Culture, and the EFRE-fund (2013 FE 9075), and XLifeSciences (X-Kidneys, DD 0290-20). German Federal Ministry of Education and Research (01KG1104), German Research Foundation (GR1852/6-1), Thuringian Ministry for Education, Science, and Culture, and the EFRE-fund (2013 FE 9075), and XLifeSciences (X-Kidneys, DD 0290-20).
Collapse
Affiliation(s)
- Heidrun Rhode
- Jena University Hospital, Institute of Biochemistry I, Nonnenplan 2-4, 07743 Jena, Germany
| | - Baerbel Tautkus
- Jena University Hospital, Institute of Biochemistry I, Nonnenplan 2-4, 07743 Jena, Germany
| | - Friederike Weigel
- Jena University Hospital, Department of Pediatrics and Adolescent Medicine, Am Klinikum 1, 07747 Jena, Germany
| | - Julia Schitke
- Jena University Hospital, Department of Pediatrics and Adolescent Medicine, Am Klinikum 1, 07747 Jena, Germany
| | - Oliver Metzing
- Jena University Hospital, Department of Pediatrics and Adolescent Medicine, Am Klinikum 1, 07747 Jena, Germany
| | - Jan Boeckhaus
- Clinics for Nephrology and Rheumatology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany
| | - Wieland Kiess
- Hospital for Children and Adolescents, University of Leipzig, Liebigstr. 20a, 04103 Leipzig, Germany
| | - Oliver Gross
- Clinics for Nephrology and Rheumatology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany
| | - Axel Dost
- Jena University Hospital, Department of Pediatrics and Adolescent Medicine, Am Klinikum 1, 07747 Jena, Germany
| | - Ulrike John-Kroegel
- Jena University Hospital, Department of Pediatrics and Adolescent Medicine, Am Klinikum 1, 07747 Jena, Germany
| |
Collapse
|
|
11
|
Laudon A, Wang Z, Zou A, Sharma R, Ji J, Kim C, Qian Y, Ye Q, Chen H, Henderson JM, Zhang C, Kolachalama VB, Lu W. Digital pathology assessment of kidney glomerular filtration barrier ultrastructure in an animal model of podocytopathy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.14.599097. [PMID: 38948787 PMCID: PMC11212870 DOI: 10.1101/2024.06.14.599097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Background Transmission electron microscopy (TEM) images can visualize kidney glomerular filtration barrier ultrastructure, including the glomerular basement membrane (GBM) and podocyte foot processes (PFP). Podocytopathy is associated with glomerular filtration barrier morphological changes observed experimentally and clinically by measuring GBM or PFP width. However, these measurements are currently performed manually. This limits research on podocytopathy disease mechanisms and therapeutics due to labor intensiveness and inter-operator variability. Methods We developed a deep learning-based digital pathology computational method to measure GBM and PFP width in TEM images from the kidneys of Integrin-Linked Kinase (ILK) podocyte-specific conditional knockout (cKO) mouse, an animal model of podocytopathy, compared to wild-type (WT) control mouse. We obtained TEM images from WT and ILK cKO littermate mice at 4 weeks old. Our automated method was composed of two stages: a U-Net model for GBM segmentation, followed by an image processing algorithm for GBM and PFP width measurement. We evaluated its performance with a 4-fold cross-validation study on WT and ILK cKO mouse kidney pairs. Results Mean (95% confidence interval) GBM segmentation accuracy, calculated as Jaccard index, was 0.73 (0.70-0.76) for WT and 0.85 (0.83-0.87) for ILK cKO TEM images. Automated and manual GBM width measurements were similar for both WT (p=0.49) and ILK cKO (p=0.06) specimens. While automated and manual PFP width measurements were similar for WT (p=0.89), they differed for ILK cKO (p<0.05) specimens. WT and ILK cKO specimens were morphologically distinguishable by manual GBM (p<0.05) and PFP (p<0.05) width measurements. This phenotypic difference was reflected in the automated GBM (p<0.05) more than PFP (p=0.06) widths. Conclusions These results suggest that certain automated measurements enabled via deep learning-based digital pathology tools could distinguish healthy kidneys from those with podocytopathy. Our proposed method provides high-throughput, objective morphological analysis and could facilitate podocytopathy research and translate into clinical diagnosis.
Collapse
Affiliation(s)
- Aksel Laudon
- Department of Biomedical Engineering, Boston University, Boston, MA, USA
- Nephrology Section, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, MA, USA
| | - Zhaoze Wang
- Department of Biomedical Engineering, Boston University, Boston, MA, USA
| | - Anqi Zou
- Computational Biomedicine Section, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, MA, USA
| | - Richa Sharma
- Nephrology Section, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, MA, USA
| | - Jiayi Ji
- Nephrology Section, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, MA, USA
| | - Connor Kim
- Department of Biomedical Engineering, Boston University, Boston, MA, USA
| | - Yingzhe Qian
- Department of Biomedical Engineering, Boston University, Boston, MA, USA
| | - Qin Ye
- Department of Biomedical Engineering, Boston University, Boston, MA, USA
| | - Hui Chen
- Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, MA, USA
| | - Joel M Henderson
- Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, MA, USA
| | - Chao Zhang
- Computational Biomedicine Section, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, MA, USA
| | - Vijaya B Kolachalama
- Computational Biomedicine Section, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, MA, USA
- Department of Computer Science and Faculty of Computing & Data Sciences, Boston University, Boston, MA, USA
| | - Weining Lu
- Nephrology Section, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, MA, USA
- Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, MA, USA
| |
Collapse
|
|
12
|
Mou X, Shah J, Roye Y, Du C, Musah S. An ultrathin membrane mediates tissue-specific morphogenesis and barrier function in a human kidney chip. SCIENCE ADVANCES 2024; 10:eadn2689. [PMID: 38838141 PMCID: PMC11152122 DOI: 10.1126/sciadv.adn2689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 04/30/2024] [Indexed: 06/07/2024]
Abstract
Organ-on-chip (OOC) systems are revolutionizing tissue engineering by providing dynamic models of tissue structure, organ-level function, and disease phenotypes using human cells. However, nonbiological components of OOC devices often limit the recapitulation of in vivo-like tissue-tissue cross-talk and morphogenesis. Here, we engineered a kidney glomerulus-on-a-chip that recapitulates glomerular morphogenesis and barrier function using a biomimetic ultrathin membrane and human-induced pluripotent stem cells. The resulting chip comprised a proximate epithelial-endothelial tissue interface, which reconstituted the selective molecular filtration function of healthy and diseased kidneys. In addition, fenestrated endothelium was successfully induced from human pluripotent stem cells in an OOC device, through in vivo-like paracrine signaling across the ultrathin membrane. Thus, this device provides a dynamic tissue engineering platform for modeling human kidney-specific morphogenesis and function, enabling mechanistic studies of stem cell differentiation, organ physiology, and pathophysiology.
Collapse
Affiliation(s)
- Xingrui Mou
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27710, USA
| | - Jessica Shah
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27710, USA
| | - Yasmin Roye
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27710, USA
| | - Carolyn Du
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27710, USA
| | - Samira Musah
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27710, USA
- Center for Biomolecular and Tissue Engineering, Duke University, Durham, NC 27710, USA
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
- Department of Cell Biology, Duke University, Durham, NC 27710, USA
- Affiliate Faculty of the Developmental and Stem Cell Biology Program, Duke Regeneration Center, Duke MEDx Initiative, Duke University, Durham, NC 27710, USA
| |
Collapse
|
|
13
|
Haydak J, Azeloglu EU. Role of biophysics and mechanobiology in podocyte physiology. Nat Rev Nephrol 2024; 20:371-385. [PMID: 38443711 DOI: 10.1038/s41581-024-00815-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/30/2024] [Indexed: 03/07/2024]
Abstract
Podocytes form the backbone of the glomerular filtration barrier and are exposed to various mechanical forces throughout the lifetime of an individual. The highly dynamic biomechanical environment of the glomerular capillaries greatly influences the cell biology of podocytes and their pathophysiology. Throughout the past two decades, a holistic picture of podocyte cell biology has emerged, highlighting mechanobiological signalling pathways, cytoskeletal dynamics and cellular adhesion as key determinants of biomechanical resilience in podocytes. This biomechanical resilience is essential for the physiological function of podocytes, including the formation and maintenance of the glomerular filtration barrier. Podocytes integrate diverse biomechanical stimuli from their environment and adapt their biophysical properties accordingly. However, perturbations in biomechanical cues or the underlying podocyte mechanobiology can lead to glomerular dysfunction with severe clinical consequences, including proteinuria and glomerulosclerosis. As our mechanistic understanding of podocyte mechanobiology and its role in the pathogenesis of glomerular disease increases, new targets for podocyte-specific therapeutics will emerge. Treating glomerular diseases by targeting podocyte mechanobiology might improve therapeutic precision and efficacy, with potential to reduce the burden of chronic kidney disease on individuals and health-care systems alike.
Collapse
Affiliation(s)
- Jonathan Haydak
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Evren U Azeloglu
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| |
Collapse
|
|
14
|
Altman J, Bai S, Purohit S, White J, Steed D, Liu S, Hopkins D, She JX, Sharma A, Zhi W. A candidate panel of eight urinary proteins shows potential of early diagnosis and risk assessment for diabetic kidney disease in type 1 diabetes. J Proteomics 2024; 300:105167. [PMID: 38574989 DOI: 10.1016/j.jprot.2024.105167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 03/22/2024] [Accepted: 04/01/2024] [Indexed: 04/06/2024]
Abstract
Diabetic kidney disease (DKD) poses a significant health challenge for individuals with diabetes. At its initial stages, DKD often presents asymptomatically, and the standard for non-invasive diagnosis, the albumin-creatinine ratio (ACR), employs discrete categorizations (normal, microalbuminuria, macroalbuminuria) with limitations in sensitivity and specificity across diverse population cohorts. Single biomarker reliance further restricts the predictive value in clinical settings. Given the escalating prevalence of diabetes, our study uses proteomic technologies to identify novel urinary proteins as supplementary DKD biomarkers. A total of 158 T1D subjects provided urine samples, with 28 (15 DKD; 13 non-DKD) used in the discovery stage and 131 (45 DKD; 40 pDKD; 46 non-DKD) used in the confirmation. We identified eight proteins (A1BG, AMBP, AZGP1, BTD, RBP4, ORM2, GM2A, and PGCP), all of which demonstrated excellent area-under-the-curve (AUC) values (0.959 to 0.995) in distinguishing DKD from non-DKD. Furthermore, this multi-marker panel successfully segregated the most ambiguous group (microalbuminuria) into three distinct clusters, with 80% of subjects aligning either as DKD or non-DKD. The remaining 20% exhibited continued uncertainty. Overall, the use of these candidate urinary proteins allowed for the better classification of DKD and offered potential for significant improvements in the early identification of DKD in T1D populations.
Collapse
Affiliation(s)
- Jeremy Altman
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA 30912, USA.
| | - Shan Bai
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA 30912, USA.
| | - Sharad Purohit
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA 30912, USA; Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
| | - John White
- Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
| | - Dennis Steed
- Southeastern Endocrine and Diabetes, Atlanta, GA 30076, USA
| | - Su Liu
- Department of Endocrinology, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, Jiangsu Province
| | - Diane Hopkins
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA 30912, USA; Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
| | - Jin-Xiong She
- Jinfiniti Precision Medicine, Augusta, GA 30901, USA.
| | - Ashok Sharma
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA 30912, USA; Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Department of Population Health Sciences, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
| | - Wenbo Zhi
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA 30912, USA; Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
| |
Collapse
|
|
15
|
Mann EA, Alexander K, Beaton W, Roe EB, Grant A, Shadman KA. Screening for Nephropathy in Pediatric Type 2 Diabetes: Quality Improvement to Increase Nephropathy Screening. Pediatr Qual Saf 2024; 9:e734. [PMID: 38807582 PMCID: PMC11132389 DOI: 10.1097/pq9.0000000000000734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 04/17/2024] [Indexed: 05/30/2024] Open
Abstract
Background Screening for early detection of microalbuminuria signaling kidney disease should begin as early as the time of diagnosis of youth-onset type 2 diabetes. This quality improvement initiative aimed to standardize urine nephropathy screening in pediatric patients with type 2 diabetes at a tertiary academic medical center and increase a baseline screening rate of 56%-75% over 6 months (September 2022-February 2023) and sustain that increase for 6 months (March through August 2023). Methods A multi-disciplinary team used quality improvement methods and iterative Plan-Do-Study-Act cycles. Targeted interventions included previsit planning workflow, education, and a new-onset triage protocol. The team collected data at baseline and prospectively by reviewing electronic medical records. The primary outcome measure was pediatric type 2 diabetes clinic visits in diabetes clinic with urine nephropathy screening before or on the visit date. Results A total of 121 youth were scheduled for T2D clinic visits between September 2021 and August 2023. The mean age was 14.5 years, and 60% were women, 40% were non-Hispanic Black, 28% were Hispanic/Latino, and 15% reported Spanish as their preferred language. Following the interventions of this project, urine nephropathy screening increased from 56% to 75%, and this change was sustained for 6 months. Conclusions Interventions focused on efficient recognition of the population needing screening, coordinated internal processes around screening, a shared understanding between all stakeholders, and practical support in the healthcare system increased urine nephropathy screening with sustained improvement.
Collapse
Affiliation(s)
- Elizabeth A. Mann
- From the Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisc
| | - Kelsi Alexander
- From the Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisc
| | | | | | - Amy Grant
- Cincinnati Children’s Hospital Medical Center, James M. Anderson Center for Health Systems Excellence
| | - Kristin A. Shadman
- From the Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisc
| |
Collapse
|
|
16
|
Xia J, Huang Y, Ma M, Liu F, Cao B. Downregulating lncRNA MIAT attenuates apoptosis of podocytes exposed to high glucose. Acta Diabetol 2024; 61:451-460. [PMID: 38072843 DOI: 10.1007/s00592-023-02213-w] [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: 07/10/2023] [Accepted: 11/08/2023] [Indexed: 03/27/2024]
Abstract
AIMS Diabetic nephropathy (DN), a destructive complication of diabetes mellitus (DM), is one of the leading causes of end-stage renal disease (ESRD). This study aimed to investigate the role of long non-coding RNA (lncRNA) MIAT in high-glucose (HG)-induced podocyte injury associated with DN. METHODS Three human kidney podocyte (HKP) cultures were treated with HG to mimic DN. Expression of lncRNA MIAT, podocyte-specific and injury-related proteins, and apoptosis were assessed before and after MIAT knockdown using MIAT shRNAs. RESULTS MIAT expression was upregulated in HKPs in response to glucose stress. HG treatment resulted in a significant increase in the apoptotic rate, Bax level, and levels of injury-related proteins desmin, fibroblast-specific protein 1 (FSP-1), and smooth muscle α-actin (α-SMA), and a significant reduction in Bcl-2 levels and the levels of podocyte-specific proteins synaptopodin and podocin. Transfection of HKPs with shRNAs significantly reduced MIAT levels (p < 0.05) and attenuated apoptosis in HG-medium. Correspondingly, the levels of synaptopodin and podocin were upregulated, and desmin, FSP-1, and α-SMA were reduced (p < 0.05). Western blot analysis also showed that anti-apoptotic active caspase-3 and Bax and proapoptotic Bcl-2 were elevated and decreased, respectively, after MIAT knockdown, suggesting that apoptosis pathways are deactivated after MIAT downregulation. CONCLUSIONS High glucose upregulates MIAT level in HKPs and induces cellular injury. Knockdown of MIAT alleviates the injury likely via deactivating apoptosis pathways.
Collapse
Affiliation(s)
- Jiayi Xia
- Department of Endocrinology, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou, China
| | - Yan Huang
- Department of Medical Insurance, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou, China
| | - Min Ma
- Department of Gynecology, Graduate School of Guizhou, University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou, China
| | - Fang Liu
- Department of Coloproctology, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou, China.
| | - Bo Cao
- Department of Coloproctology, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou, China.
| |
Collapse
|
|
17
|
Kotsiubiichuk Z, Antoniv A, Kanovska L, Mandryk O. Correction of endothelial dysfunction in patients with type 2 diabetes mellitus, diabetic kidney disease and non-alcoholic steatohepatitis. INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (UKRAINE) 2024; 20:1-6. [DOI: 10.22141/2224-0721.20.1.2024.1350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Background. Non-alcoholic fatty liver disease and chronic kidney disease are public health concerns worldwide due to their increasing prevalence, adverse prognosis, and health care burden. The purpose of the study was to determine the probable effect of a combination of metformin, rosuvastatin, essential phospholipids and quercetin on the blood lipids, endothelial function, fibrinolysis system and platelet hemostasis, which are factors for the progression of nonalcoholic steatohepatitis. Materials and methods. Studies were performed on the dynamics of treatment in 60 patients with non-alcoholic fatty liver disease, type 2 diabetes mellitus and diabetic kidney disease (stage I–III). Depending on the prescribed treatment at random, the examined patients were divided into 2 groups. Twenty-eight persons of the first group received a low-calorie diet with dietary restrictions, essential phospholipids, metformin hydrochloride, rosuvastatin. Thirty-two patients from the second group received quercetin in addition to similar dietary recommendations, essential phospholipids, hypoglycemic and hypolipidemic therapy. The mean age of patients was 53.80 ± 3.52 years. The comparison group consisted of 30 healthy individuals of the corresponding age. Results. To evaluate the degree of endothelial-protective effect of quercetin on the background of the recommended protocol therapy, markers of endothelial dysfunction, fibrinolysis and platelet hemostasis were studied. NO content significantly reduced (1.7 times) in patients of group 2 before treatment, increased by 1.5 times (p < 0.05). This can be explained by the effect of quercetin, as well as the use of metformin, which reduces the degree of insulin resistance and the level of hyperlipidemia. Conclusions. The effectiveness of a combination therapy for non-alcoholic steatohepatitis and type 2 diabetes mellitus with diabetic kidney disease using essential phospholipids, statins and metformin with the addition of quercetin is higher than that of traditional therapy, as it significantly restores the functional state of the endothelium, eliminates the phenomena of hypercoagulation syndrome without the additional prescription of antiplatelet agents.
Collapse
|
|
18
|
Kelada MN, Elagawany A, El Sekily NM, El Mallah M, Abou Nazel MW. Protective Effect of Platelet-Rich Plasma on Cisplatin-Induced Nephrotoxicity in Adult Male Albino Rats: Histological and Immunohistochemical Study. Biol Trace Elem Res 2024; 202:1067-1083. [PMID: 37420147 PMCID: PMC10803452 DOI: 10.1007/s12011-023-03742-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Accepted: 06/19/2023] [Indexed: 07/09/2023]
Abstract
Cisplatin is a potent antineoplastic drug that is used for treatment of many solid tumors. It has a wide range of adverse effects. Nephrotoxicity is the most common one of them. Platelet-rich plasma (PRP) is an autologous human plasma that activates the tissue regeneration through cell proliferation and differentiation. Study the role of PRP in amelioration of cisplatin-induced nephrotoxicity on the kidney of adult male albino rats by biochemical, morphometric, histological, and immunohistochemical studies. Thirty-five adult male albino rats were used. Thirty rats were included as experimental group and five were used to obtain the PRP. The experimental group was classified into as follows: control group which received 1mL of sterile saline by intraperitoneal injection (IP), cisplatin-treated group which received cisplatin 7.5 mg/kg IP in a single dose and cisplatin and PRP-treated group rats received cisplatin 7.5 mg/kg single IP dose followed by 1ml of PRP IP after 24 h of cisplatin injection. There was a significant increase in urea and creatinine levels in cisplatin-treated group in comparison to the control and the PRP groups. The kidneys of cisplatin-treated group showed distorted renal structure, where specimens of PRP-treated group revealed restoration of the classical appearance of the renal tissue similar to the control group. PRP has protective effects on renal structure and functions and it helps to ameliorate the histological changes induced by cisplatin.
Collapse
Affiliation(s)
- Melad N Kelada
- Anatomy and Embryology department, Faculty of Medicine, University of Alexandria, Alexandria, Egypt.
| | - Amany Elagawany
- Anatomy and Embryology department, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
| | - Nancy Mohamed El Sekily
- Anatomy and Embryology department, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
| | - Mona El Mallah
- Anatomy and Embryology department, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
| | - Maha W Abou Nazel
- Histology and Cell Biology Department, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
| |
Collapse
|
|
19
|
Lou Y, Li PH, Liu XQ, Wang TX, Liu YL, Chen CC, Ma KL. ITGAM-mediated macrophages contribute to basement membrane damage in diabetic nephropathy and atherosclerosis. BMC Nephrol 2024; 25:72. [PMID: 38413872 PMCID: PMC10900706 DOI: 10.1186/s12882-024-03505-1] [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: 10/29/2023] [Accepted: 02/15/2024] [Indexed: 02/29/2024] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) and atherosclerosis (AS) are prevalent and severe complications associated with diabetes, exhibiting lesions in the basement membrane, an essential component found within the glomerulus, tubules, and arteries. These lesions contribute significantly to the progression of both diseases, however, the precise underlying mechanisms, as well as any potential shared pathogenic processes between them, remain elusive. METHODS Our study analyzed transcriptomic profiles from DN and AS patients, sourced from the Gene Expression Omnibus database. A combination of integrated bioinformatics approaches and machine learning models were deployed to identify crucial genes connected to basement membrane lesions in both conditions. The role of integrin subunit alpha M (ITGAM) was further explored using immune infiltration analysis and genetic correlation studies. Single-cell sequencing analysis was employed to delineate the expression of ITGAM across different cell types within DN and AS tissues. RESULTS Our analyses identified ITGAM as a key gene involved in basement membrane alterations and revealed its primary expression within macrophages in both DN and AS. ITGAM was significantly correlated with tissue immune infiltration within these diseases. Furthermore, the expression of genes encoding core components of the basement membrane was influenced by the expression level of ITGAM. CONCLUSION Our findings suggest that macrophages may contribute to basement membrane lesions in DN and AS through the action of ITGAM. Moreover, therapeutic strategies that target ITGAM may offer potential avenues to mitigate basement membrane lesions in these two diabetes-related complications.
Collapse
Affiliation(s)
- Yude Lou
- Department of Nephrology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Peng Hui Li
- Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Xiao Qi Liu
- Department of Nephrology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Tian Xiang Wang
- Department of Nephrology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Yi Lan Liu
- Department of Nephrology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Chen Chen Chen
- Department of Basic Medicine Sciences, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Kun Ling Ma
- Department of Nephrology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
| |
Collapse
|
|
20
|
Tang C, Yang C, Wang P, Li L, Lin Y, Yi Q, Tang F, Liu L, Zhou W, Liu D, Zhang L, Yuan X. Identification and Validation of Glomeruli Cellular Senescence-Related Genes in Diabetic Nephropathy by Multiomics. Adv Biol (Weinh) 2024; 8:e2300453. [PMID: 37957539 DOI: 10.1002/adbi.202300453] [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: 08/27/2023] [Revised: 10/08/2023] [Indexed: 11/15/2023]
Abstract
Accumulating evidence indicates that cellular premature senescence of the glomerulus, including endothelial cells, mesangial cells, and podocytes leads to diabetic nephropathy (DN), and DN is regarded as a clinical model of premature senescence. However, the role of cellular senescence-associated genes in the glomerulus in DN progression remains unclear. Therefore, this work aims to identify and validate potential cellular aging-related genes in the glomerulus in DN to provide novel clues for DN treatment based on anti-aging. The microarray GSE96804 dataset, including 41 diabetic glomeruli and 20 control glomeruli, is retrieved from the Gene Expression Omnibus (GEO) database and cellular senescence-related genes (CSRGs) are obtained from the GeneCards database and literature reports. Subsequently, PPI, GO, and KEGG enrichment are analyzed by screening the intersection between differentially expressed genes (DEGs) and CSRGs. scRNA-seq dataset GSE127235 is used to verify core genes expression in glomerulocytes of mice. Finally, db/db mice are utilized to validate the hub gene expression in the glomeruli, and high glucose-induced mesangial cells are used to confirm key gene expression. This study reveals that FOS and ZFP36 may play an anti-aging role in DN to ameliorate cell intracellular premature aging in mesangial cells of glomeruli.
Collapse
Affiliation(s)
- Chunyin Tang
- Evidence-Based Pharmacy Center, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, 610000, China
- College of Life Science, Mudanjiang Medical University, Mudanjiang, 157000, China
| | - Chunsong Yang
- Evidence-Based Pharmacy Center, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, 610000, China
| | - Peiwen Wang
- College of Life Science, Mudanjiang Medical University, Mudanjiang, 157000, China
| | - Luxin Li
- College of Life Science, Mudanjiang Medical University, Mudanjiang, 157000, China
| | - Yunzhu Lin
- Evidence-Based Pharmacy Center, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, 610000, China
| | - Qiusha Yi
- Evidence-Based Pharmacy Center, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, 610000, China
| | - Fengru Tang
- Evidence-Based Pharmacy Center, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, 610000, China
| | - Lantao Liu
- Postgraduate Department, Mudanjiang Medical University, Mudanjiang, 157011, China
| | - Wei Zhou
- Evidence-Based Pharmacy Center, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, 610000, China
| | - Dongwen Liu
- Evidence-Based Pharmacy Center, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, 610000, China
| | - Lingli Zhang
- Evidence-Based Pharmacy Center, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, 610000, China
| | - Xiaohuan Yuan
- College of Life Science, Mudanjiang Medical University, Mudanjiang, 157000, China
| |
Collapse
|
|
21
|
Gao F, Zhou Y, Yu B, Xie H, Shi Y, Zhang X, Liu H. QiDiTangShen granules alleviates diabetic nephropathy podocyte injury: A network pharmacology study and experimental validation in vivo and vitro. Heliyon 2024; 10:e23535. [PMID: 38223704 PMCID: PMC10784173 DOI: 10.1016/j.heliyon.2023.e23535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 12/05/2023] [Accepted: 12/05/2023] [Indexed: 01/16/2024] Open
Abstract
Background QiDiTangShen granules (QDTS), a traditional Chinese medicine (TCM) compound prescription, have remarkable efficacy in diabetic nephropathy (DN) patients, and their pharmacological mechanism needs further exploration. Methods According to the active ingredients and targets of the QDTS in the TCMSP database, the network pharmacology of QDTS was investigated. The potential active ingredients were chosen based on the oral bioavailability and the drug similarity index. At the same time, targets for DN-related disease were obtained from GeneCards, OMIM, PharmGKB, TTD, and DrugBank. The TCM-component-target network and the protein-protein interaction (PPI) network were constructed with the Cytoscape and STRING platforms, respectively, and then the core targets of DN were selected with CytoNCA. GO and KEGG enrichment analysis using R software. Molecular docking to identify the core targets of QDTS for DN. In vivo, db/db mice were treated as DN models, and the urine microalbuminuria, the pathological changes in the kidney and the protein expression levels of p-PI3K, p-Akt, JUN, nephrin and synaptopodin were detected by immunohistochemistry, immunofluorescence method and Western blotting. After QDTS was used in vitro, the protein expression of mouse podocyte clone-5 (MPC5) cells was detected by immunohistochemistry, immunofluorescence and Western blot. Results Through network pharmacology analysis, 153 potential targets for DN in QDTS were identified, 19 of which were significant. The KEGG enrichment analysis indicated that QDTS might have therapeutic effects on IL-17, TNF, AGE-RAGE, PI3K-Akt, HIF-1, and EGFR through interfering with Akt1 and JUN. The main active ingredients in QDTS are quercetin, β-sitosterol, stigmasterol and kaempferol. Both in vivo and in vitro studies showed that QDTS could decrease the urine microalbuminuria and renal pathology of db/db mice, and alleviate podocyte injuries through the PI3K/Akt signaling pathway. Conclusion Through network pharmacology, in vivo and in vitro experiments, QDTS has been shown to improve the urine microalbuminuria and renal pathology in DN, and to reduce podocyte damage via the PI3K/Akt pathway.
Collapse
Affiliation(s)
- Fei Gao
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
- Department of Endocrinology and Nephrology, Renal Research Institute of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Ying Zhou
- Department of Endocrinology and Nephrology, Renal Research Institute of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Borui Yu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
- Department of Endocrinology and Nephrology, Renal Research Institute of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Huidi Xie
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, 100853, China
| | - Yang Shi
- Department of Endocrinology and Nephrology, Renal Research Institute of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Xianhui Zhang
- Health Management Center, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Hongfang Liu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
- Department of Endocrinology and Nephrology, Renal Research Institute of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| |
Collapse
|
|
22
|
Hassan MH, Galal O, Sakhr HM, Kamaleldeen EB, Zekry NF, Fateen E, Toghan R. Profile of plasma free amino acids, carnitine and acylcarnitines, and JAK2 v617f mutation as potential metabolic markers in children with type 1 diabetic nephropathy. Biomed Chromatogr 2023; 37:e5747. [PMID: 37728037 DOI: 10.1002/bmc.5747] [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: 04/01/2023] [Revised: 08/28/2023] [Accepted: 08/29/2023] [Indexed: 09/21/2023]
Abstract
Fifty diabetic nephropathy (DN) children with type 1 diabetes mellitus (T1DM) and 50 healthy matched controls were included. Chromatographic assays of 14 amino acids, free carnitine and 27 carnitine esters using high-performance liquid chromatography/electrospray ionization-mass spectroscopy, and genetic testing for JAK2v617f mutation using real-time PCR were performed. Patients had significantly lower levels of tyrosine, branched-chain amino acids (BCAAs), and BCAA/AAA (aromatic chain amino acids) ratios, glycine, arginine, ornithine, free carnitine and some carnitine esters (C5, 6, 12 and 16) and higher phenylalanine, phenylalanine/tyrosine ratio and C18 compared with the controls and in the macro-albuminuria vs. the microalbuminuria group (p < 0.05 for all) except for free carnitine. Plasma carnitine was negatively correlated with eGFR (r = -0.488, p = 0.000). There were significant positive correlations between tyrosine with UACR ratio (r = 0.296, p = 0.037). The plasma BCAA/AAA ratio showed significant negative correlations with UACR (r = -0.484, p = 0.000). There was a significantly higher frequency of the JAK2V617F gene mutation in diabetic nephropathy patients compared with the control group and in macro-albuminuria than the microalbuminuria group (p = 0.000) for both. When monitoring children with T1DM, plasma free amino acids and acylcarnitine profiles should be considered, especially if they have tested positive for JAK2V617F for the early diagnosis of DN.
Collapse
Affiliation(s)
- Mohammed H Hassan
- Department of Medical Biochemistry, Faculty of Medicine, South Valley University, Qena, Egypt
| | - Omyma Galal
- Medical Physiology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Hala M Sakhr
- Department of Pediatrics, Faculty of Medicine, South Valley University, Qena, Egypt
| | - Eman B Kamaleldeen
- Department of Pediatrics, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Nadia Farouk Zekry
- Medical Physiology Department, Faculty of Medicine, South Valley University, Qena, Egypt
| | - Ekram Fateen
- Department of Biochemical Genetics, National Research Center, Cairo, Egypt
| | - Rana Toghan
- Medical Physiology Department, Faculty of Medicine, South Valley University, Qena, Egypt
| |
Collapse
|
|
23
|
Liu Z, Yang J, Du M, Xin W. Functioning and mechanisms of PTMs in renal diseases. Front Pharmacol 2023; 14:1238706. [PMID: 38074159 PMCID: PMC10702752 DOI: 10.3389/fphar.2023.1238706] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 11/13/2023] [Indexed: 12/22/2024] Open
Abstract
Post-translational modifications (PTMs) are crucial epigenetic mechanisms that regulate various cellular biological processes. The use of mass spectrometry (MS)-proteomics has led to the discovery of numerous novel types of protein PTMs, such as acetylation, crotonylation, 2-hydroxyisobutyrylation, β-hydroxybutyrylation, protein propionylation and butyrylation, succinylation, malonylation, lactylation, and histone methylation. In this review, we specifically highlight the molecular mechanisms and roles of various histone and some non-histone PTMs in renal diseases, including diabetic kidney disease. PTMs exhibit diverse effects on renal diseases, which can be either protective or detrimental, depending on the specific type of protein PTMs and their respective targets. Different PTMs activate various signaling pathways in diverse renal pathological conditions, which could provide novel insights for studying epigenetic mechanisms and developing potential therapeutic strategies for renal diseases.
Collapse
Affiliation(s)
- Zhenzhen Liu
- Medical Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Jian Yang
- Medical Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Minghui Du
- Biomedical Science College, Shandong First Medical University, Jinan, China
| | - Wei Xin
- Medical Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| |
Collapse
|
|
24
|
Albrecht M, Sticht C, Wagner T, Hettler SA, De La Torre C, Qiu J, Gretz N, Albrecht T, Yard B, Sleeman JP, Garvalov BK. The crosstalk between glomerular endothelial cells and podocytes controls their responses to metabolic stimuli in diabetic nephropathy. Sci Rep 2023; 13:17985. [PMID: 37863933 PMCID: PMC10589299 DOI: 10.1038/s41598-023-45139-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 10/16/2023] [Indexed: 10/22/2023] Open
Abstract
In diabetic nephropathy (DN), glomerular endothelial cells (GECs) and podocytes undergo pathological alterations, which are influenced by metabolic changes characteristic of diabetes, including hyperglycaemia (HG) and elevated methylglyoxal (MGO) levels. However, it remains insufficiently understood what effects these metabolic factors have on GEC and podocytes and to what extent the interactions between the two cell types can modulate these effects. To address these questions, we established a co-culture system in which GECs and podocytes were grown together in close proximity, and assessed transcriptional changes in each cell type after exposure to HG and MGO. We found that HG and MGO had distinct effects on gene expression and that the effect of each treatment was markedly different between GECs and podocytes. HG treatment led to upregulation of "immediate early response" genes, particularly those of the EGR family, as well as genes involved in inflammatory responses (in GECs) or DNA replication/cell cycle (in podocytes). Interestingly, both HG and MGO led to downregulation of genes related to extracellular matrix organisation in podocytes. Crucially, the transcriptional responses of GECs and podocytes were dependent on their interaction with each other, as many of the prominently regulated genes in co-culture of the two cell types were not significantly changed when monocultures of the cells were exposed to the same stimuli. Finally, the changes in the expression of selected genes were validated in BTBR ob/ob mice, an established model of DN. This work highlights the molecular alterations in GECs and podocytes in response to the key diabetic metabolic triggers HG and MGO, as well as the central role of GEC-podocyte crosstalk in governing these responses.
Collapse
Affiliation(s)
- Michael Albrecht
- European Center for Angioscience (ECAS), Medical Faculty Mannheim of the University of Heidelberg, Ludolf-Krehl-Strasse 13-17, 68167, Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim of the University of Heidelberg, Ludolf-Krehl-Strasse 13-17, 68167, Mannheim, Germany
| | - Carsten Sticht
- Center of Medical Research, Bioinformatics and Statistics, Medical Faculty Mannheim of the University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
- NGS Core Facility, Medical Faculty Mannheim of the University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Tabea Wagner
- European Center for Angioscience (ECAS), Medical Faculty Mannheim of the University of Heidelberg, Ludolf-Krehl-Strasse 13-17, 68167, Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim of the University of Heidelberg, Ludolf-Krehl-Strasse 13-17, 68167, Mannheim, Germany
| | - Steffen A Hettler
- Department of Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology and Pneumology, Fifth Department of Medicine, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany
| | - Carolina De La Torre
- Center of Medical Research, Bioinformatics and Statistics, Medical Faculty Mannheim of the University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
- NGS Core Facility, Medical Faculty Mannheim of the University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Jiedong Qiu
- Department of Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology and Pneumology, Fifth Department of Medicine, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany
| | - Norbert Gretz
- Center of Medical Research, Bioinformatics and Statistics, Medical Faculty Mannheim of the University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Thomas Albrecht
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg, Germany
| | - Benito Yard
- Department of Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology and Pneumology, Fifth Department of Medicine, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany
| | - Jonathan P Sleeman
- European Center for Angioscience (ECAS), Medical Faculty Mannheim of the University of Heidelberg, Ludolf-Krehl-Strasse 13-17, 68167, Mannheim, Germany.
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim of the University of Heidelberg, Ludolf-Krehl-Strasse 13-17, 68167, Mannheim, Germany.
- Institute of Biological and Chemical Systems - Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology Campus North, Building 319, Hermann-Von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany.
| | - Boyan K Garvalov
- European Center for Angioscience (ECAS), Medical Faculty Mannheim of the University of Heidelberg, Ludolf-Krehl-Strasse 13-17, 68167, Mannheim, Germany.
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim of the University of Heidelberg, Ludolf-Krehl-Strasse 13-17, 68167, Mannheim, Germany.
| |
Collapse
|
|
25
|
Loesch A. Vasa Vasorum in Saphenous Vein for CABG: A Review of Morphological Characteristics. Braz J Cardiovasc Surg 2023; 38:e20230045. [PMID: 37797088 PMCID: PMC10548833 DOI: 10.21470/1678-9741-2023-0045] [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: 02/06/2023] [Accepted: 02/23/2023] [Indexed: 10/07/2023] Open
Abstract
This short article discusses selected scanning electron microscope and transmission electron microscope features of vasa vasorum including pericytes and basement membrane of the human saphenous vein (SV) harvested with either conventional (CON) or no-touch (NT) technique for coronary artery bypass grafting. Scanning electron microscope data shows the general damage to vasa vasorum of CON-SV, while the transmission electron microscope data presents ultrastructural features of the vasa in more detail. Hence there are some features suggesting pericyte involvement in the contraction of vasa blood vessels, particularly in CON-SV. Other features associated with the vasa vasorum of both CON-SV and NT-SV preparations include thickened and/or multiplied layers of the basement membrane. In some cases, multiple layers of basement membrane embrace both pericyte and vasa microvessel making an impression of a "unit" made by basement membrane-pericyte-endothelium/microvessel. It can be speculated that this structural arrangement has an effect on the contractile and/or relaxing properties of the vessels involved. Endothelial colocalization of immunoreactive inducible nitric oxide synthase and endothelin-1 can be observed (with laser confocal microscope) in some of the vasa microvessels. It can be speculated that this phenomenon, particularly of the expression of inducible nitric oxide synthase, might be related to structurally changed vasa vessels, e.g., with expanded basement membrane. Fine physiological relationships between vasa vasorum endothelium, basement membrane, pericyte, and perivascular nerves have yet to be uncovered in the detail needed for better understanding of the cells'specific effects in SV preparations for coronary artery bypass grafting.
Collapse
Affiliation(s)
- Andrzej Loesch
- Research Department of Inflammation, Centre for Rheumatology and
Connective Tissue Diseases, Division of Medicine, University College London, London,
United Kingdom
| |
Collapse
|
|
26
|
Marassi M, Fadini GP. The cardio-renal-metabolic connection: a review of the evidence. Cardiovasc Diabetol 2023; 22:195. [PMID: 37525273 PMCID: PMC10391899 DOI: 10.1186/s12933-023-01937-x] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 07/22/2023] [Indexed: 08/02/2023] Open
Abstract
Type 2 diabetes (T2D), cardiovascular disease (CVD) and chronic kidney disease (CKD), are recognized among the most disruptive public health issues of the current century. A large body of evidence from epidemiological and clinical research supports the existence of a strong interconnection between these conditions, such that the unifying term cardio-metabolic-renal (CMR) disease has been defined. This coexistence has remarkable epidemiological, pathophysiologic, and prognostic implications. The mechanisms of hyperglycemia-induced damage to the cardio-renal system are well validated, as are those that tie cardiac and renal disease together. Yet, it remains controversial how and to what extent CVD and CKD can promote metabolic dysregulation. The aim of this review is to recapitulate the epidemiology of the CMR connections; to discuss the well-established, as well as the putative and emerging mechanisms implicated in the interplay among these three entities; and to provide a pathophysiological background for an integrated therapeutic intervention aiming at interrupting this vicious crosstalks.
Collapse
Affiliation(s)
- Marella Marassi
- Department of Medicine, Division of Metabolic Diseases, University of Padova, Via Giustiniani 2, 35128, Padua, Italy
| | - Gian Paolo Fadini
- Department of Medicine, Division of Metabolic Diseases, University of Padova, Via Giustiniani 2, 35128, Padua, Italy.
- Veneto Institute of Molecular Medicine, 35129, Padua, Italy.
| |
Collapse
|
|
27
|
Kaverina N, Schweickart RA, Chan GC, Maggiore JC, Eng DG, Zeng Y, McKinzie SR, Perry HS, Ali A, O’Connor C, Pereira BMV, Theberge AB, Vaughan JC, Loretz CJ, Chang A, Hukriede NA, Bitzer M, Pippin JW, Wessely O, Shankland SJ. Inhibiting NLRP3 signaling in aging podocytes improves their life- and health-span. Aging (Albany NY) 2023; 15:6658-6689. [PMID: 37487005 PMCID: PMC10415579 DOI: 10.18632/aging.204897] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 07/06/2023] [Indexed: 07/26/2023]
Abstract
The decrease in the podocyte's lifespan and health-span that typify healthy kidney aging cause a decrease in their normal structure, physiology and function. The ability to halt and even reverse these changes becomes clinically relevant when disease is superimposed on an aged kidney. RNA-sequencing of podocytes from middle-aged mice showed an inflammatory phenotype with increases in the NLRP3 inflammasome, signaling for IL2/Stat5, IL6 and TNF, interferon gamma response, allograft rejection and complement, consistent with inflammaging. Furthermore, injury-induced NLRP3 signaling in podocytes was further augmented in aged mice compared to young ones. The NLRP3 inflammasome (NLRP3, Caspase-1, IL1β IL-18) was also increased in podocytes of middle-aged humans. Higher transcript expression for NLRP3 in human glomeruli was accompanied by reduced podocyte density and increased global glomerulosclerosis and glomerular volume. Pharmacological inhibition of NLRP3 with MCC950, or gene deletion, reduced podocyte senescence and the genes typifying aging in middle-aged mice, which was accompanied by an improved podocyte lifespan and health-span. Moreover, modeling the injury-dependent increase in NLRP3 signaling in human kidney organoids confirmed the anti-senescence effect of MC9950. Finally, NLRP3 also impacted liver aging. Together, these results suggest a critical role for the NLRP3 inflammasome in podocyte and liver aging.
Collapse
Affiliation(s)
- Natalya Kaverina
- Division of Nephrology, University of Washington, Seattle, WA 98109, USA
| | - R. Allen Schweickart
- Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44106, USA
| | - Gek Cher Chan
- Department of Medicine, Division of Nephrology, National University Hospital, Singapore
| | - Joseph C. Maggiore
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Diana G. Eng
- Division of Nephrology, University of Washington, Seattle, WA 98109, USA
| | - Yuting Zeng
- Department of Chemistry, University of Washington, Seattle, WA 98109, USA
| | - Sierra R. McKinzie
- Division of Nephrology, University of Washington, Seattle, WA 98109, USA
| | - Hannah S. Perry
- Department of Chemistry, University of Washington, Seattle, WA 98109, USA
| | - Adilijiang Ali
- Department of Chemistry, University of Washington, Seattle, WA 98109, USA
| | | | | | | | - Joshua C. Vaughan
- Department of Chemistry, University of Washington, Seattle, WA 98109, USA
- Department of Physiology and Biophysics, University of Washington, Seattle, WA 98109, USA
| | - Carol J. Loretz
- Division of Nephrology, University of Washington, Seattle, WA 98109, USA
| | - Anthony Chang
- Department of Pathology, University of Chicago, Chicago, IL 60637, USA
| | - Neil A. Hukriede
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Markus Bitzer
- Division of Nephrology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jeffrey W. Pippin
- Division of Nephrology, University of Washington, Seattle, WA 98109, USA
| | - Oliver Wessely
- Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44106, USA
| | - Stuart J. Shankland
- Division of Nephrology, University of Washington, Seattle, WA 98109, USA
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA
| |
Collapse
|
|
28
|
Smith DW, Azadi A, Lee CJ, Gardiner BS. Spatial composition and turnover of the main molecules in the adult glomerular basement membrane. Tissue Barriers 2023; 11:2110798. [PMID: 35959954 PMCID: PMC10364650 DOI: 10.1080/21688370.2022.2110798] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 07/31/2022] [Accepted: 08/03/2022] [Indexed: 10/15/2022] Open
Abstract
The glomerular basement membrane (GBM) is an important tissue structure in kidney function. It is the membrane through which filtrate and solutes must pass to reach the nephron tubules. This review focuses on the spatial location of the main extracellular matrix components of the GBM. It also attempts to explain this organization in terms of their synthesis, transport, and loss. The picture that emerges is that the collagen IV and laminin content of GBM are in a very slow dynamic disequilibrium, leading to GBM thickening with age, and in contrast, some heparan sulfate proteoglycans are in a dynamic equilibrium with a very rapid turnover (i.e. half-life measured in ~hours) and flow direction against the flow of filtrate. The highly rapid heparan sulfate turnover may serve several roles, including an unclogging mechanism for the GBM, compressive stiffness of the GBM fiber network, and/or enabling podocycte-endothelial crosstalk against the flow of filtrate.
Collapse
Affiliation(s)
- David W. Smith
- Faculty of Engineering and Mathematical Sciences, The University of Western Australia, Crawley, Western Australia, Australia
| | - Azin Azadi
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Western Australia, Australia
| | - Chang-Joon Lee
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Western Australia, Australia
| | - Bruce S. Gardiner
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Western Australia, Australia
| |
Collapse
|
|
29
|
Wang D, Ferrell N. In Vitro Models to Evaluate Molecular Permeability of the Kidney Filtration Barrier. Methods Mol Biol 2023; 2664:41-53. [PMID: 37423981 DOI: 10.1007/978-1-0716-3179-9_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/11/2023]
Abstract
The glomerular basement membrane (GBM) is an important component of the kidney filtration barrier. The ability to evaluate the molecular transport properties of the GBM and determining how changes in the structure, composition, and mechanical properties of the GBM regulate its size selective transport properties may provide additional insight into glomerular function. This chapter details a method for making in vitro models of the glomerular filtration barrier using animal-derived decellularized glomeruli. FITC-labelled Ficoll is used as a filtration probe to evaluate the molecular transport properties during passive diffusion and under applied pressure. These systems can serve as a platform to evaluate the molecular permeability of basement membrane systems using conditions that simulate normal or pathophysiological conditions.
Collapse
Affiliation(s)
- Dan Wang
- Department of Internal Medicine, Division of Nephrology, Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Nicholas Ferrell
- Department of Internal Medicine, Division of Nephrology, Ohio State University Wexner Medical Center, Columbus, OH, USA.
| |
Collapse
|
|
30
|
Wang D, Sant S, Lawless C, Ferrell N. A kidney proximal tubule model to evaluate effects of basement membrane stiffening on renal tubular epithelial cells. Integr Biol (Camb) 2022; 14:171-183. [PMID: 36573280 DOI: 10.1093/intbio/zyac016] [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: 01/20/2022] [Revised: 09/21/2022] [Accepted: 11/06/2022] [Indexed: 12/28/2022]
Abstract
The kidney tubule consists of a single layer of epithelial cells supported by the tubular basement membrane (TBM), a thin layer of specialized extracellular matrix (ECM). The mechanical properties of the ECM are important for regulating a wide range of cell functions including proliferation, differentiation and cell survival. Increased ECM stiffness plays a role in promoting multiple pathological conditions including cancer, fibrosis and heart disease. How changes in TBM mechanics regulate tubular epithelial cell behavior is not fully understood. Here we introduce a cell culture system that utilizes in vivo-derived TBM to investigate cell-matrix interactions in kidney proximal tubule cells. Basement membrane mechanics was controlled using genipin, a biocompatibility crosslinker. Genipin modification resulted in a dose-dependent increase in matrix stiffness. Crosslinking had a marginal but statistically significant impact on the diffusive molecular transport properties of the TBM, likely due to a reduction in pore size. Both native and genipin-modified TBM substrates supported tubular epithelial cell growth. Cells were able to attach and proliferate to form confluent monolayers. Tubular epithelial cells polarized and assembled organized cell-cell junctions. Genipin modification had minimal impact on cell viability and proliferation. Genipin stiffened TBM increased gene expression of pro-fibrotic cytokines and altered gene expression for N-cadherin, a proximal tubular epithelial specific cell-cell junction marker. This work introduces a new cell culture model for cell-basement membrane mechanobiology studies that utilizes in vivo-derived basement membrane. We also demonstrate that TBM stiffening affects tubular epithelial cell function through altered gene expression of cell-specific differentiation markers and induced increased expression of pro-fibrotic growth factors.
Collapse
Affiliation(s)
- Dan Wang
- Department of Internal Medicine, Division of Nephrology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Snehal Sant
- Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Craig Lawless
- Wellcome Trust Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Nicholas Ferrell
- Department of Internal Medicine, Division of Nephrology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| |
Collapse
|
|
31
|
Wu Q, Yan R, Yang H, Wang Y, Zhang C, Zhang J, Cui Z, Wang Y, Sun W. Qing-Re-Xiao-Zheng-Yi-Qi formula relieves kidney damage and activates mitophagy in diabetic kidney disease. Front Pharmacol 2022; 13:992597. [PMID: 36605399 PMCID: PMC9807870 DOI: 10.3389/fphar.2022.992597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 12/06/2022] [Indexed: 12/24/2022] Open
Abstract
Introduction: Qing-Re-Xiao-Zheng-Yi-Qi Formula is an effective prescription in diabetic kidney disease treatment, we have confirmed the efficacy of Qing-Re-Xiao-Zheng therapy in diabetic kidney disease through clinical trials. In this study, we investigated the mechanisms of Qing-Re-Xiao-Zheng-Yi-Qi Formula in the treatment of diabetic kidney disease. Methods: We used Vanquish UHPLCTM to analyze the chemical profiling of Qing-Re-Xiao-Zheng-Yi-Qi Formula freeze-dried powder. We constructed diabetic kidney disease rat models induced by unilateral nephrectomy and high-dose streptozocin injection. We examined blood urea nitrogen, serum creatinine, serum glucose, total cholesterol, triglyceride, serum total protein, albumin, alanine aminotransferase, aspartate aminotransferase and 24 h urinary total protein in diabetic kidney disease rats. The renal pathological changes were observed by HE, Masson, PAS stanning and transmission electron microscopy. The levels of fibrosis-related proteins and mitophagy-related proteins were detected by western blot analysis. We also conducted an immunofluorescence co-localization analysis on podocytes to further investigate the effect of Qing-Re-Xiao-Zheng-Yi-Qi Formula treatment on mitophagy. Results: A total of 27 constituents in Qing-Re-Xiao-Zheng-Yi-Qi Formula were tentatively identified. We found PINK1/Parkin-mediated mitophagy was inhibited in diabetic kidney disease. Qing-Re-Xiao-Zheng-Yi-Qi Formula treatment could raise body weight and reduce renal index, reduce proteinuria, improve glycolipid metabolic disorders, ameliorate renal fibrosis, and reduce the expression of Col Ⅳ and TGF-β1 in diabetic kidney disease rats. Qing-Re-Xiao-Zheng-Yi-Qi Formula treatment could also increase the expression of nephrin, activate mitophagy and protect podocytes in diabetic kidney disease rats and high glucose cultured podocytes. Conclusion: PINK1/Parkin-mediated mitophagy was inhibited in diabetic kidney disease, and Qing-Re-Xiao-Zheng-Yi-Qi Formula treatment could not only ameliorate pathological damage, but also promote mitophagy to protect podocytes in diabetic kidney disease.
Collapse
Affiliation(s)
- Qiaoru Wu
- Department of Nephrology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, BJ, China
| | - Runze Yan
- Department of Nephrology, Beijing Dongcheng First People’s Hospital, Beijing, BJ, China
| | - Hanwen Yang
- Department of Nephrology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, BJ, China
| | - Yixuan Wang
- Department of Nephrology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, BJ, China
| | - Chao Zhang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, BJ, China
| | - Jiale Zhang
- Department of Nephrology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, BJ, China
| | - Zhaoli Cui
- Department of Nephrology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, BJ, China
| | - Yaoxian Wang
- Beijing University of Chinese Medicine, Beijing, BJ, China,*Correspondence: Yaoxian Wang, ; Weiwei Sun,
| | - Weiwei Sun
- Department of Nephrology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, BJ, China,*Correspondence: Yaoxian Wang, ; Weiwei Sun,
| |
Collapse
|
|
32
|
Punyaratabandhu N, Dechadilok P, Triampo W, Katavetin P. Hydrodynamic model for renal microvascular filtration: Effects of physiological and hemodynamic changes on glomerular size-selectivity. Microcirculation 2022; 29:e12779. [PMID: 35879876 DOI: 10.1111/micc.12779] [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: 07/19/2021] [Revised: 06/25/2022] [Accepted: 07/21/2022] [Indexed: 12/30/2022]
Abstract
OBJECTIVE The first step in renal urine formation is ultrafiltration across the glomerular barrier. The change in its nanostructure has been associated with nephrotic syndromes. Effects of physiological and hemodynamic factor alterations associated with diabetic nephropathy (DN) on glomerular permselectivity are examined through a mathematical model employing low-Reynolds-number hydrodynamics and hindered transport theory. METHODS Glomerular capillaries are represented as networks of cylindrical tubes with multilayered walls. Glomerular basement membrane (GBM) is a fibrous medium with bimodal fiber sizes. Epithelial slit fiber spacing follows a lognormal distribution based on reported electron micrographs with the highest resolution. Endothelial fenestrae are filled with fibers the size of glycosaminoglycans (GAGs). Effects of fiber-macromolecule steric and hydrodynamic interactions are included. Focusing on diabetic nephropathy, the physiological and hemodynamic factors employed in the computation are those reported for healthy humans and patients with early-but-overt diabetic nephropathy. The macromolecule concentration is obtained as a finite element solution of the convection-diffusion equation. RESULTS Computed sieving coefficients averaged along the capillary length agree well with ficoll sieving coefficients from studies in humans for most solute radii. GBM thickening and the loss of the slit diaphragm hardly affect glomerular permselectivity. GAG volume fraction reduction in the endothelial fenestrae, however, significantly increases macromolecule filtration. Increased renal plasma flow rate (RPF), glomerular hypertension, and reduction of lumen osmotic pressure cause a slight sieving coefficient decrease. These effects are amplified by an increased macromolecule size. CONCLUSION Our results indicate that glomerular hypertension and the reduction in the oncotic pressure decreases glomerular macromolecule filtration. Reduction of RPF and changes in the glomerular barrier structure associated with DN, however, increase the solute sieving. Damage to GAGs caused by hyperglycemia is likely to be the most prominent factor affecting glomerular size-selectivity.
Collapse
Affiliation(s)
| | - Panadda Dechadilok
- Department of Physics, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
| | - Wannapong Triampo
- Thailand Center of Excellence in Physics CHE, Bangkok, Thailand.,Department of Physics, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Pisut Katavetin
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| |
Collapse
|
|
33
|
Muntean C, Starcea IM, Banescu C. Diabetic kidney disease in pediatric patients: A current review. World J Diabetes 2022; 13:587-599. [PMID: 36159227 PMCID: PMC9412860 DOI: 10.4239/wjd.v13.i8.587] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 06/13/2022] [Accepted: 07/11/2022] [Indexed: 02/05/2023] Open
Abstract
In the last decades, a significant increase in the incidence of diabetic kidney disease (DKD) was observed concomitant with rising diabetes mellitus (DM) incidence. Kidney disease associated with DM in children and adolescents is represented by persistent albuminuria, arterial hypertension, progressive decline in estimated glomerular filtration rate to end-stage renal disease and increased cardiovascular and all-cause morbidity and mortality of these conditions. In medical practice, the common and still the "gold standard" marker for prediction and detection of diabetic kidney involvement in pediatric diabetes is represented by microalbuminuria screening even if it has low specificity to detect early stages of DKD. There are some known limitations in albuminuria value as a predictor biomarker for DKD, as not all diabetic children with microalbuminuria or macroalbuminuria will develop end-stage renal disease. As tubular damage occurs before the glomerular injury, tubular biomarkers are superior to the glomerular ones. Therefore, they may serve for early detection of DKD in both type 1 DM and type 2 DM. Conventional and new biomarkers to identify diabetic children and adolescents at risk of renal complications at an early stage as well as renoprotective strategies are necessary to delay the progression of kidney disease to end-stage kidney disease. New biomarkers and therapeutic strategies are discussed as timely diagnosis and therapy are critical in the pediatric diabetic population.
Collapse
Affiliation(s)
- Carmen Muntean
- Department of Pediatrics I, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology of Târgu Mures, Târgu Mures 540142, Romania
| | - Iuliana Magdalena Starcea
- Department of IVth Pediatrics, University of Medicine and Pharmacy “Grigore T. Popa”, Iasi 700115, Romania
| | - Claudia Banescu
- Center for Advanced Medical and Pharmaceutical Research, University of Medicine, Pharmacy, Sciences and Technology of Târgu Mureș, Mureș, Târgu Mures 540142, Romania
| |
Collapse
|
|
34
|
Cheng X, Zhou T, He Y, Xie Y, Xu Y, Huang W. The role and mechanism of butyrate in the prevention and treatment of diabetic kidney disease. Front Microbiol 2022; 13:961536. [PMID: 36016798 PMCID: PMC9396028 DOI: 10.3389/fmicb.2022.961536] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetic kidney disease (DKD) remains the leading cause of the end-stage renal disease and is a major burden on the healthcare system. The current understanding of the mechanisms responsible for the progression of DKD recognizes the involvement of oxidative stress, low-grade inflammation, and fibrosis. Several circulating metabolites that are the end products of the fermentation process, released by the gut microbiota, are known to be associated with systemic immune-inflammatory responses and kidney injury. This phenomenon has been recognized as the “gut–kidney axis.” Butyrate is produced predominantly by gut microbiota fermentation of dietary fiber and undigested carbohydrates. In addition to its important role as a fuel for colonic epithelial cells, butyrate has been demonstrated to ameliorate obesity, diabetes, and kidney diseases via G-protein coupled receptors (GPCRs). It also acts as an epigenetic regulator by inhibiting histone deacetylase (HDAC), up-regulation of miRNAs, or induction of the histone butyrylation and autophagy processes. This review aims to outline the existing literature on the treatment of DKD by butyrate in animal models and cell culture experiments, and to explore the protective effects of butyrate on DKD and the underlying molecular mechanism.
Collapse
Affiliation(s)
- Xi Cheng
- Department of Endocrinology and Metabolism, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Affiliated Hospital of Southwest Medical University, Luzhou, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, China
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China
| | - Tingting Zhou
- Department of Endocrinology and Metabolism, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Affiliated Hospital of Southwest Medical University, Luzhou, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, China
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China
- Tingting Zhou,
| | - Yanqiu He
- Department of Endocrinology and Metabolism, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Affiliated Hospital of Southwest Medical University, Luzhou, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, China
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China
| | - Yumei Xie
- Sichuan Clinical Research Center for Nephropathy, Luzhou, China
| | - Yong Xu
- Department of Endocrinology and Metabolism, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Affiliated Hospital of Southwest Medical University, Luzhou, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, China
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China
- *Correspondence: Yong Xu,
| | - Wei Huang
- Department of Endocrinology and Metabolism, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Affiliated Hospital of Southwest Medical University, Luzhou, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, China
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China
- Wei Huang,
| |
Collapse
|
|
35
|
Aboolian A, Urner S, Roden M, Jha JC, Jandeleit-Dahm K. Diabetic Kidney Disease: From Pathogenesis to Novel Treatment Possibilities. Handb Exp Pharmacol 2022; 274:269-307. [PMID: 35318511 DOI: 10.1007/164_2021_576] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
One of the microvascular complications of diabetes is diabetic kidney disease (DKD), often leading to end stage renal disease (ESRD) in which patients require costly dialysis or transplantation. The silent onset and irreversible progression of DKD are characterized by a steady decline of the estimated glomerular filtration rate, with or without concomitant albuminuria. The diabetic milieu allows the complex pathophysiology of DKD to enter a vicious cycle by inducing the synthesis of excessive amounts of reactive oxygen species (ROS) causing oxidative stress, inflammation, and fibrosis. As no cure is available, intensive research is required to develop novel treatments possibilities. This chapter provides an overview of the important pathomechanisms identified in diabetic kidney disease, the currently established therapies, as well as recently developed novel therapeutic strategies in DKD.
Collapse
Affiliation(s)
- Ara Aboolian
- Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Sofia Urner
- Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Michael Roden
- Department of Endocrinology and Diabetology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
- Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Centre for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
| | - Jay Chandra Jha
- Department of Diabetes, Monash University, Melbourne, VIC, Australia
| | - Karin Jandeleit-Dahm
- Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
- Department of Diabetes, Monash University, Melbourne, VIC, Australia.
| |
Collapse
|
|
36
|
Zhao T, Li M, Xiang Q, Lie B, Chen D, Wang W, Li X, Xu T, Zhang X, Li Y, Dong R, Du X, Wang Y, Yang J, He B, Zhu Q, Duan T, Li Z, Xu Y. Yishen Huashi Granules Ameliorated the Development of Diabetic Nephropathy by Reducing the Damage of Glomerular Filtration Barrier. Front Pharmacol 2022; 13:872940. [PMID: 35935814 PMCID: PMC9353776 DOI: 10.3389/fphar.2022.872940] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 06/21/2022] [Indexed: 02/03/2023] Open
Abstract
Background: Diabetic nephropathy (DN) is one of the most common complications of diabetes and the primary cause of end-stage renal disease. At present, renin–angiotensin–aldosterone system (RAAS) blockers have been applied as first-class drugs to restrain development of DN; however, its long-term effect is limited. Recent evidence has shown definite effects of Chinese medicine on DN. Yishen Huashi (YSHS) granule is a traditional Chinese Medicine prescription that has been used in the clinic to treat DN, but its mechanism is not understood. Methods: In the present study, both in vitro and in vivo studies were carried out. The DN model was induced by STZ in Wistar rats, and GEnC and HPC cell lines were applied in the in vitro study. Quality of YSHS was evaluated by LC-MS/MS. A metabolomic study of urine was carried out by LC-MS; influence of YSHS on composition of DN was analyzed by network pharmacology. Mechanism of the YSHS on DN was analyzed by Q-PCR, Western Blot, and multi-immunological methods. Results: We found YSHS administration significantly reduced levels of HbA1c and mALB. Histopathological analysis found that YSHS preserved integrity of glomerular filtration barrier by preserving viability of glomerular endothelial cells and podocytes, inhibiting glomerular fibrosis, reducing oxidative stress damage, and enhancing cross-talk among glomerular endothelial cells and podocytes. Network pharmacology, differential metabolite analysis, as well as intracellular pathway experimental study demonstrated that the PI3K/AKT/mTOR signaling pathway played a pivotal role in it. Conclusion: Our present findings supplied new understanding toward the mechanism of YSHS on inhibiting DN.
Collapse
Affiliation(s)
- Tingting Zhao
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, China
| | - Minyi Li
- Institute of Consun Co., for Chinese Medicine in Kidney Diseases, Guangdong Consun Pharmaceutical Group, Guangzhou, China
| | - Qian Xiang
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, China
| | - Beifeng Lie
- Institute of Consun Co., for Chinese Medicine in Kidney Diseases, Guangdong Consun Pharmaceutical Group, Guangzhou, China
| | - Deqi Chen
- Institute of Consun Co., for Chinese Medicine in Kidney Diseases, Guangdong Consun Pharmaceutical Group, Guangzhou, China
| | - Weiming Wang
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, China
| | - Xuling Li
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, China
| | - Tiancheng Xu
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, China
| | - Xi Zhang
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, China
| | - Yuntong Li
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, China
| | - Ruixue Dong
- State Key Laboratory of Quality Research in Chinese Medicines, School of Pharmacy, Macau University of Science and Technology, Macao, China
| | - Xinwen Du
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, China
| | - Yilin Wang
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, China
- Department of Endocrinology, Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine, Zhuhai, China
| | - Junzheng Yang
- Institute of Consun Co., for Chinese Medicine in Kidney Diseases, Guangdong Consun Pharmaceutical Group, Guangzhou, China
| | - Bao He
- Institute of Consun Co., for Chinese Medicine in Kidney Diseases, Guangdong Consun Pharmaceutical Group, Guangzhou, China
| | - Quan Zhu
- Institute of Consun Co., for Chinese Medicine in Kidney Diseases, Guangdong Consun Pharmaceutical Group, Guangzhou, China
| | - Tingting Duan
- Institute of Consun Co., for Chinese Medicine in Kidney Diseases, Guangdong Consun Pharmaceutical Group, Guangzhou, China
- *Correspondence: Tingting Duan, ; Zhenghai Li, ; Youhua Xu,
| | - Zhenghai Li
- Institute of Consun Co., for Chinese Medicine in Kidney Diseases, Guangdong Consun Pharmaceutical Group, Guangzhou, China
- *Correspondence: Tingting Duan, ; Zhenghai Li, ; Youhua Xu,
| | - Youhua Xu
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, China
- State Key Laboratory of Quality Research in Chinese Medicines, School of Pharmacy, Macau University of Science and Technology, Macao, China
- Department of Endocrinology, Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine, Zhuhai, China
- Macau University of Science and Technology Zhuhai MUST Science and Technology Research Institute, Zhuhai, China
- *Correspondence: Tingting Duan, ; Zhenghai Li, ; Youhua Xu,
| |
Collapse
|
|
37
|
Hofherr A, Williams J, Gan LM, Söderberg M, Hansen PBL, Woollard KJ. Targeting inflammation for the treatment of Diabetic Kidney Disease: a five-compartment mechanistic model. BMC Nephrol 2022; 23:208. [PMID: 35698028 PMCID: PMC9190142 DOI: 10.1186/s12882-022-02794-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 04/20/2022] [Indexed: 12/25/2022] Open
Abstract
Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. Mortality and morbidity associated with DKD are increasing with the global prevalence of type 2 diabetes. Chronic, sub-clinical, non-resolving inflammation contributes to the pathophysiology of renal and cardiovascular disease associated with diabetes. Inflammatory biomarkers correlate with poor renal outcomes and mortality in patients with DKD. Targeting chronic inflammation may therefore offer a route to novel therapeutics for DKD. However, the DKD patient population is highly heterogeneous, with varying etiology, presentation and disease progression. This heterogeneity is a challenge for clinical trials of novel anti-inflammatory therapies. Here, we present a conceptual model of how chronic inflammation affects kidney function in five compartments: immune cell recruitment and activation; filtration; resorption and secretion; extracellular matrix regulation; and perfusion. We believe that the rigorous alignment of pathophysiological insights, appropriate animal models and pathology-specific biomarkers may facilitate a mechanism-based shift from recruiting ‘all comers’ with DKD to stratification of patients based on the principal compartments of inflammatory disease activity.
Collapse
Affiliation(s)
- Alexis Hofherr
- Research and Early Clinical Development, Cardiovascular, Renal and Metabolism, AstraZeneca, BioPharmaceuticals R&D, Gothenburg, Sweden. .,Renal Division, Department of Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
| | - Julie Williams
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolic, AstraZeneca, BioPharmaceuticals R&D, Gothenburg, UK
| | - Li-Ming Gan
- Research and Early Clinical Development, Cardiovascular, Renal and Metabolism, AstraZeneca, BioPharmaceuticals R&D, Gothenburg, Sweden.,Department of Molecular and Clinical Medicine, Department of Cardiology, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Magnus Söderberg
- Cardiovascular, Renal and Metabolic Safety, Clinical Pharmacology and Safety Sciences, AstraZeneca, BioPharmaceuticals R&D, Gothenburg, Sweden
| | - Pernille B L Hansen
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolic, AstraZeneca, BioPharmaceuticals R&D, Gothenburg, UK.,Wallenberg Center for Molecular and Translational Medicine, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Kevin J Woollard
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolic, AstraZeneca, BioPharmaceuticals R&D, Gothenburg, UK. .,Centre for Inflammatory Disease, Imperial College London, London, UK.
| |
Collapse
|
|
38
|
Bian C, Zhang R, Wang Y, Li J, Song Y, Guo D, Gao J, Ren H. Sirtuin 6 affects glucose reabsorption and gluconeogenesis in type 1 diabetes via FoxO1. Mol Cell Endocrinol 2022; 547:111597. [PMID: 35157928 DOI: 10.1016/j.mce.2022.111597] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 02/07/2022] [Accepted: 02/10/2022] [Indexed: 12/20/2022]
Abstract
AIM The purpose of this study was to explore the expression changes of Sirtuin 6 in diabetic renal tissues and the molecular mechanisms affecting renal tubular gluconeogenesis and reabsorption. METHODS The type 1 diabetic C57BL/6 mice model as well as high glucose cultured proximal tubular cells and cell lines were established. Sirt6 siRNA, the SGLT2 inhibitor (dapagliflozin), and insulin were pre-treated to make Sirtuin 6 levels, gluconeogenesis, and reabsorption changes. Immunofluorescence was used for Sirtuin 6 renal localization, and molecular biological detection was adopted for transcription factors, FoxO1, transporters (SGLT2 and GLUT2) as well as rate-limiting enzyme. Nuclear/plasma proteins were extracted to detect Sirtuin 6 and FoxO1 levels in the subcellular structure. RESULTS Sirtuin 6 was decreased in STZ-induced diabetic renal outer medulla, and lower both in high glucose-induced primary proximal tubular cells and cell lines. Sirtuin 6 reversed the glucose reabsorption and gluconeogenesis effect via regulating FoxO1 and affecting nuclear translocation of FoxO1 in high glucose-induced proximal tubular cells. CONCLUSION Sirtuin 6 affects renal glucose reabsorption and gluconeogenesis in type 1 diabetes by regulating FoxO1 nuclear import.
Collapse
Affiliation(s)
- Che Bian
- Department of Endocrinology and Metabolism, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Ruijing Zhang
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
| | - Yuxia Wang
- Department of Endocrinology and Metabolism, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Jia Li
- Department of Endocrinology and Metabolism, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Yuling Song
- Department of Endocrinology and Metabolism, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Dan Guo
- Department of Endocrinology and Metabolism, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Jing Gao
- Department of Gerontology, Xin Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Huiwen Ren
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, Liaoning, China.
| |
Collapse
|
|
39
|
Mechanisms of podocyte injury and implications for diabetic nephropathy. Clin Sci (Lond) 2022; 136:493-520. [PMID: 35415751 PMCID: PMC9008595 DOI: 10.1042/cs20210625] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 02/25/2022] [Accepted: 03/25/2022] [Indexed: 02/06/2023]
Abstract
Albuminuria is the hallmark of both primary and secondary proteinuric glomerulopathies, including focal segmental glomerulosclerosis (FSGS), obesity-related nephropathy, and diabetic nephropathy (DN). Moreover, albuminuria is an important feature of all chronic kidney diseases (CKDs). Podocytes play a key role in maintaining the permselectivity of the glomerular filtration barrier (GFB) and injury of the podocyte, leading to foot process (FP) effacement and podocyte loss, the unifying underlying mechanism of proteinuric glomerulopathies. The metabolic insult of hyperglycemia is of paramount importance in the pathogenesis of DN, while insults leading to podocyte damage are poorly defined in other proteinuric glomerulopathies. However, shared mechanisms of podocyte damage have been identified. Herein, we will review the role of haemodynamic and oxidative stress, inflammation, lipotoxicity, endocannabinoid (EC) hypertone, and both mitochondrial and autophagic dysfunction in the pathogenesis of the podocyte damage, focussing particularly on their role in the pathogenesis of DN. Gaining a better insight into the mechanisms of podocyte injury may provide novel targets for treatment. Moreover, novel strategies for boosting podocyte repair may open the way to podocyte regenerative medicine.
Collapse
|
|
40
|
Pereira PR, Carrageta DF, Oliveira PF, Rodrigues A, Alves MG, Monteiro MP. Metabolomics as a tool for the early diagnosis and prognosis of diabetic kidney disease. Med Res Rev 2022; 42:1518-1544. [PMID: 35274315 DOI: 10.1002/med.21883] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 01/26/2022] [Accepted: 02/22/2022] [Indexed: 01/21/2023]
Abstract
Diabetic kidney disease (DKD) is one of the most prevalent comorbidities of diabetes mellitus and the leading cause of the end-stage renal disease (ESRD). DKD results from chronic exposure to hyperglycemia, leading to progressive alterations in kidney structure and function. The early development of DKD is clinically silent and when albuminuria is detected the lesions are often at advanced stages, leading to rapid kidney function decline towards ESRD. DKD progression can be arrested or substantially delayed if detected and addressed at early stages. A major limitation of current methods is the absence of albuminuria in non-albuminuric phenotypes of diabetic nephropathy, which becomes increasingly prevalent and lacks focused therapy. Metabolomics is an ever-evolving omics technology that enables the study of metabolites, downstream products of every biochemical event that occurs in an organism. Metabolomics disclosures complex metabolic networks and provide knowledge of the very foundation of several physiological or pathophysiological processes, ultimately leading to the identification of diseases' unique metabolic signatures. In this sense, metabolomics is a promising tool not only for the diagnosis but also for the identification of pre-disease states which would confer a rapid and personalized clinical practice. Herein, the use of metabolomics as a tool to identify the DKD metabolic signature of tubule interstitial lesions to diagnose or predict the time-course of DKD will be discussed. In addition, the proficiency and limitations of the currently available high-throughput metabolomic techniques will be discussed.
Collapse
Affiliation(s)
- Pedro R Pereira
- Clinical and Experimental Endocrinology, UMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS, School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.,ITR - Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal.,Department of Nephrology, Centro Hospitalar de Trás-os-Montes e Alto Douro (CHTMAD, EPE), Vila Real, Portugal
| | - David F Carrageta
- Clinical and Experimental Endocrinology, UMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS, School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.,ITR - Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal
| | - Pedro F Oliveira
- Department of Chemistry, QOPNA & LAQV, University of Aveiro, Aveiro, Portugal
| | - Anabela Rodrigues
- Department of Nephrology and Department of Clinical Pathology, Santo António General Hospital (Hospital Center of Porto, EPE), Porto, Portugal.,Nephrology, Dialysis and Transplantation, UMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal
| | - Marco G Alves
- Clinical and Experimental Endocrinology, UMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS, School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.,ITR - Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal.,Biotechnology of Animal and Human Reproduction (TechnoSperm), Institute of Food and Agricultural Technology, University of Girona, Girona, Spain.,Department of Biology, Unit of Cell Biology, Faculty of Sciences, University of Girona, Girona, Spain
| | - Mariana P Monteiro
- Clinical and Experimental Endocrinology, UMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS, School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.,ITR - Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal
| |
Collapse
|
|
41
|
Al-Ruwaili M, Jarrar B, Jarrar Q, Al-Doaiss A, Alshehri M, Melhem W. Renal ultrastructural damage induced by chronic exposure to copper oxide nanomaterials: Electron microscopy study. Toxicol Ind Health 2022; 38:80-91. [PMID: 35209751 DOI: 10.1177/07482337211062674] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Copper oxide nanomaterials are used in many biomedical, agricultural, environmental, and industrial sectors with potential risk to human health and the environment. The present study was conducted to determine the renal ultrastructural damage caused by 25 nm CuO nanoparticles in renal tissues. Adult healthy male Wister Albino rats (Rattus norvegicus) were administered 35 intraperitoneal injections of CuO nanoparticles (2 mg/kg). Ultrastructural changes were evaluated using transmission electron microscopy techniques. The renal tissues of rats with subchronic exposure to CuO nanoparticles demonstrated glomerular alterations that included hypertrophic endothelial cells, dilated capillaries and occlusions, podocyte hypertrophy, pedicle disorganization, mesangial cell hyperplasia, and crystalloid precipitation. Moreover, the treated renal cells exhibited mitochondrial swelling and crystolysis, cytoplasmic vacoulization, lysosomal hypertrophy, apoptotic activity, endoplasmic reticulum dilatation, nuclear deformity, chromatin dissolution, and basement membrane thickening. In addition, disruption and disorganization of the renal cells microvilli together with cystolic inclusions were also detected. It was concluded from the present findings that CuO nanoparticles could interact with the components of the renal tissues in ways that could cause ultrastructural injury, suggesting renal tissue pathophysiology. Additional studies are suggested for a better understanding the nanotoxicity of CuO nanomaterials.
Collapse
Affiliation(s)
- Meshref Al-Ruwaili
- College of Applied Medical Sciences, 248389Aljouf University, Saudi Arabia
| | - Bashir Jarrar
- Nanobiolgy Unit, College of Applied Medical Sciences, 123295Jerash University, Jordan
| | - Qais Jarrar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, 108568Isra University, Amman, Jordan
| | - Amin Al-Doaiss
- Department of Biology, College of Science, 48144King Khalid University, Abha, Saudi Arabia
| | - Mohammed Alshehri
- Department of Biology, College of Science, 48144King Khalid University, Abha, Saudi Arabia
| | - Walid Melhem
- Electron Microscopy Unit, College of Medicine, 114800King Faisal University, Al-Hasa, Saudi Arabia
| |
Collapse
|
|
42
|
Wu H, Norton V, Cui K, Zhu B, Bhattacharjee S, Lu YW, Wang B, Shan D, Wong S, Dong Y, Chan SL, Cowan D, Xu J, Bielenberg DR, Zhou C, Chen H. Diabetes and Its Cardiovascular Complications: Comprehensive Network and Systematic Analyses. Front Cardiovasc Med 2022; 9:841928. [PMID: 35252405 PMCID: PMC8891533 DOI: 10.3389/fcvm.2022.841928] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 01/18/2022] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus is a worldwide health problem that usually comes with severe complications. There is no cure for diabetes yet and the threat of these complications is what keeps researchers investigating mechanisms and treatments for diabetes mellitus. Due to advancements in genomics, epigenomics, proteomics, and single-cell multiomics research, considerable progress has been made toward understanding the mechanisms of diabetes mellitus. In addition, investigation of the association between diabetes and other physiological systems revealed potentially novel pathways and targets involved in the initiation and progress of diabetes. This review focuses on current advancements in studying the mechanisms of diabetes by using genomic, epigenomic, proteomic, and single-cell multiomic analysis methods. It will also focus on recent findings pertaining to the relationship between diabetes and other biological processes, and new findings on the contribution of diabetes to several pathological conditions.
Collapse
Affiliation(s)
- Hao Wu
- Department of Surgery, Vascular Biology Program, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | - Vikram Norton
- Department of Surgery, Vascular Biology Program, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | - Kui Cui
- Department of Surgery, Vascular Biology Program, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | - Bo Zhu
- Department of Surgery, Vascular Biology Program, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | - Sudarshan Bhattacharjee
- Department of Surgery, Vascular Biology Program, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | - Yao Wei Lu
- Department of Surgery, Vascular Biology Program, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | - Beibei Wang
- Department of Surgery, Vascular Biology Program, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | - Dan Shan
- Department of Surgery, Vascular Biology Program, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | - Scott Wong
- Department of Surgery, Vascular Biology Program, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | - Yunzhou Dong
- Department of Surgery, Vascular Biology Program, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | - Siu-Lung Chan
- Department of Surgery, Vascular Biology Program, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | - Douglas Cowan
- Department of Surgery, Vascular Biology Program, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | - Jian Xu
- Department of Medicine, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma, OK, United States
| | - Diane R Bielenberg
- Department of Surgery, Vascular Biology Program, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | - Changcheng Zhou
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
| | - Hong Chen
- Department of Surgery, Vascular Biology Program, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| |
Collapse
|
|
43
|
Sharma M, Singh V, Sharma R, Koul A, McCarthy ET, Savin VJ, Joshi T, Srivastava T. Glomerular Biomechanical Stress and Lipid Mediators during Cellular Changes Leading to Chronic Kidney Disease. Biomedicines 2022; 10:407. [PMID: 35203616 PMCID: PMC8962328 DOI: 10.3390/biomedicines10020407] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 01/31/2022] [Accepted: 02/04/2022] [Indexed: 02/04/2023] Open
Abstract
Hyperfiltration is an important underlying cause of glomerular dysfunction associated with several systemic and intrinsic glomerular conditions leading to chronic kidney disease (CKD). These include obesity, diabetes, hypertension, focal segmental glomerulosclerosis (FSGS), congenital abnormalities and reduced renal mass (low nephron number). Hyperfiltration-associated biomechanical forces directly impact the cell membrane, generating tensile and fluid flow shear stresses in multiple segments of the nephron. Ongoing research suggests these biomechanical forces as the initial mediators of hyperfiltration-induced deterioration of podocyte structure and function leading to their detachment and irreplaceable loss from the glomerular filtration barrier. Membrane lipid-derived polyunsaturated fatty acids (PUFA) and their metabolites are potent transducers of biomechanical stress from the cell surface to intracellular compartments. Omega-6 and ω-3 long-chain PUFA from membrane phospholipids generate many versatile and autacoid oxylipins that modulate pro-inflammatory as well as anti-inflammatory autocrine and paracrine signaling. We advance the idea that lipid signaling molecules, related enzymes, metabolites and receptors are not just mediators of cellular stress but also potential targets for developing novel interventions. With the growing emphasis on lifestyle changes for wellness, dietary fatty acids are potential adjunct-therapeutics to minimize/treat hyperfiltration-induced progressive glomerular damage and CKD.
Collapse
Affiliation(s)
- Mukut Sharma
- Research and Development Service, Kansas City VA Medical Center, Kansas City, MO 64128, USA;
- Midwest Veterans’ Biomedical Research Foundation, Kansas City, MO 64128, USA; (A.K.); (V.J.S.); (T.S.)
- Department of Internal Medicine, The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, MO 66160, USA;
| | - Vikas Singh
- Neurology, Kansas City VA Medical Center, Kansas City, MO 64128, USA;
| | - Ram Sharma
- Research and Development Service, Kansas City VA Medical Center, Kansas City, MO 64128, USA;
| | - Arnav Koul
- Midwest Veterans’ Biomedical Research Foundation, Kansas City, MO 64128, USA; (A.K.); (V.J.S.); (T.S.)
| | - Ellen T. McCarthy
- Department of Internal Medicine, The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, MO 66160, USA;
| | - Virginia J. Savin
- Midwest Veterans’ Biomedical Research Foundation, Kansas City, MO 64128, USA; (A.K.); (V.J.S.); (T.S.)
| | - Trupti Joshi
- Department of Health Management and Informatics, University of Missouri, Columbia, MO 65201, USA;
| | - Tarak Srivastava
- Midwest Veterans’ Biomedical Research Foundation, Kansas City, MO 64128, USA; (A.K.); (V.J.S.); (T.S.)
- Section of Nephrology, Children’s Mercy Hospital and University of Missouri, Kansas City, MO 64108, USA
- Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri, Kansas City, MO 64108, USA
| |
Collapse
|
|
44
|
Abstract
Diabetes mellitus (DM) is gradually attacking the health and life of people all over the world. Diabetic kidney disease (DKD) is one of the most common chronic microvascular complications of DM, whose mechanism is complex and still lacks research. Sirtuin family is a class III histone deacetylase with highly conserved NAD+ binding domain and catalytic functional domain, while different N-terminal and C-terminal structures enable them to bind different deacetylated substrates to participate in the cellular NAD+ metabolism. The kidney is an organ rich in NAD+ and database exploration of literature shows that the Sirtuin family has different expression localization in renal, cellular, and subcellular structures. With the progress of modern technology, a variety of animal models and reagents for the Sirtuin family and DKD emerged. Machine learning in the literature shows that the Sirtuin family can regulate pathophysiological injury mainly in the glomerular filtration membrane, renal tubular absorption, and immune inflammation through various mechanisms such as epigenetics, multiple signaling pathways, and mitochondrial function. These mechanisms are the key nodes participating in DKD. Thus, it is of great significance for target therapy to study biological functions of the Sirtuin family and DKD regulation mechanism in-depth.
Collapse
Affiliation(s)
- Che Bian
- Department of Endocrinology and Metabolism, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Huiwen Ren
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
- *Correspondence: Huiwen Ren,
| |
Collapse
|
|
45
|
Szrejder M, Rogacka D, Piwkowska A. Purinergic P2 receptors: Involvement and therapeutic implications in diabetes-related glomerular injury. Arch Biochem Biophys 2021; 714:109078. [PMID: 34742673 DOI: 10.1016/j.abb.2021.109078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/15/2021] [Accepted: 10/30/2021] [Indexed: 02/08/2023]
Abstract
The purinergic activation of P2 receptors initiates a powerful and rapid signaling cascade that contributes to the regulation of an array of physiological and pathophysiological processes in many organs, including the kidney. P2 receptors are broadly distributed in both epithelial and vascular renal cells. Disturbances of purinergic signaling can lead to impairments in renal function. A growing body of evidence indicates changes in P2 receptor expression and nucleotide metabolism in chronic renal injury and inflammatory diseases. Increasing attention has focused on purinergic P2X7 receptors, which are not normally expressed in healthy kidney tissue but are highly expressed at sites of tissue damage and inflammation. Under hyperglycemic conditions, several mechanisms that are linked to purinergic signaling and involve nucleotide release and degradation are disrupted, resulting in the accumulation of adenosine 5'-triphosphate in the bloodstream in diabetes. Dysfunction of the purinergic system might be associated with serious vascular complications in diabetes, including diabetic nephropathy. This review summarizes our current knowledge of the role of P2 receptors in diabetes-related glomerular injury and its implications for new therapeutics for diabetic nephropathy.
Collapse
Affiliation(s)
- Maria Szrejder
- Mossakowski Medical Research Institute, Polish Academy of Sciences, Laboratory of Molecular and Cellular Nephrology, Gdańsk, Poland.
| | - Dorota Rogacka
- Mossakowski Medical Research Institute, Polish Academy of Sciences, Laboratory of Molecular and Cellular Nephrology, Gdańsk, Poland; Department of Molecular Biotechnology, University of Gdańsk, Faculty of Chemistry, Gdańsk, Poland
| | - Agnieszka Piwkowska
- Mossakowski Medical Research Institute, Polish Academy of Sciences, Laboratory of Molecular and Cellular Nephrology, Gdańsk, Poland; Department of Molecular Biotechnology, University of Gdańsk, Faculty of Chemistry, Gdańsk, Poland
| |
Collapse
|
|
46
|
Lau S, Gossen M, Lendlein A. Designing Cardiovascular Implants Taking in View the Endothelial Basement Membrane. Int J Mol Sci 2021; 22:ijms222313120. [PMID: 34884923 PMCID: PMC8658568 DOI: 10.3390/ijms222313120] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/25/2021] [Accepted: 11/29/2021] [Indexed: 12/28/2022] Open
Abstract
Insufficient endothelialization of cardiovascular grafts is a major hurdle in vascular surgery and regenerative medicine, bearing a risk for early graft thrombosis. Neither of the numerous strategies pursued to solve these problems were conclusive. Endothelialization is regulated by the endothelial basement membrane (EBM), a highly specialized part of the vascular extracellular matrix. Thus, a detailed understanding of the structure–function interrelations of the EBM components is fundamental for designing biomimetic materials aiming to mimic EBM functions. In this review, a detailed description of the structure and functions of the EBM are provided, including the luminal and abluminal interactions with adjacent cell types, such as vascular smooth muscle cells. Moreover, in vivo as well as in vitro strategies to build or renew EBM are summarized and critically discussed. The spectrum of methods includes vessel decellularization and implant biofunctionalization strategies as well as tissue engineering-based approaches and bioprinting. Finally, the limitations of these methods are highlighted, and future directions are suggested to help improve future design strategies for EBM-inspired materials in the cardiovascular field.
Collapse
Affiliation(s)
- Skadi Lau
- Institute of Active Polymers and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Hereon, Kantstraße 55, 14513 Teltow, Germany; (S.L.); (M.G.)
| | - Manfred Gossen
- Institute of Active Polymers and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Hereon, Kantstraße 55, 14513 Teltow, Germany; (S.L.); (M.G.)
| | - Andreas Lendlein
- Institute of Active Polymers and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Hereon, Kantstraße 55, 14513 Teltow, Germany; (S.L.); (M.G.)
- Institute of Chemistry, University of Potsdam, Karl-Liebknecht-Straße 25, 14476 Potsdam, Germany
- Correspondence:
| |
Collapse
|
|
47
|
Müller-Deile J, Sopel N, Ohs A, Rose V, Gröner M, Wrede C, Hegermann J, Daniel C, Amann K, Zahner G, Schiffer M. Glomerular Endothelial Cell-Derived microRNA-192 Regulates Nephronectin Expression in Idiopathic Membranous Glomerulonephritis. J Am Soc Nephrol 2021; 32:2777-2794. [PMID: 34716242 PMCID: PMC8806098 DOI: 10.1681/asn.2020121699] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 07/09/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Autoantibodies binding to podocyte antigens cause idiopathic membranous glomerulonephritis (iMGN). However, it remains elusive how autoantibodies reach the subepithelial space because the glomerular filtration barrier (GFB) is size selective and almost impermeable for antibodies. METHODS Kidney biopsies from patients with iMGN, cell culture, zebrafish, and mouse models were used to investigate the role of nephronectin (NPNT) regulating microRNAs (miRs) for the GFB. RESULTS Glomerular endothelial cell (GEC)-derived miR-192-5p and podocyte-derived miR-378a-3p are upregulated in urine and glomeruli of patients with iMGN, whereas glomerular NPNT is reduced. Overexpression of miR-192-5p and morpholino-mediated npnt knockdown induced edema, proteinuria, and podocyte effacement similar to podocyte-derived miR-378a-3p in zebrafish. Structural changes of the glomerular basement membrane (GBM) with increased lucidity, splitting, and lamellation, especially of the lamina rara interna, similar to ultrastructural findings seen in advanced stages of iMGN, were found. IgG-size nanoparticles accumulated in lucidity areas of the lamina rara interna and lamina densa of the GBM in npnt-knockdown zebrafish models. Loss of slit diaphragm proteins and severe structural impairment of the GBM were further confirmed in podocyte-specific Npnt knockout mice. GECs downregulate podocyte NPNT by transfer of miR-192-5p-containing exosomes in a paracrine manner. CONCLUSIONS Podocyte NPNT is important for proper glomerular filter function and GBM structure and is regulated by GEC-derived miR-192-5p and podocyte-derived miR-378a-3p. We hypothesize that loss of NPNT in the GBM is an important part of the initial pathophysiology of iMGN and enables autoantigenicity of podocyte antigens and subepithelial immune complex deposition in iMGN.
Collapse
Affiliation(s)
- Janina Müller-Deile
- Department of Nephrology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Nina Sopel
- Department of Nephrology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Alexandra Ohs
- Department of Nephrology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Victoria Rose
- Department of Nephrology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Marwin Gröner
- Research Center On Rare Kidney Diseases (RECORD), University Hospital Erlangen, Erlangen, Germany
| | - Christoph Wrede
- Institute of Functional and Applied Anatomy, Medizinische Hochschule Hannover, Hannover, Germany
| | - Jan Hegermann
- Institute of Functional and Applied Anatomy, Medizinische Hochschule Hannover, Hannover, Germany
| | - Christoph Daniel
- Department of Nephropathology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Kerstin Amann
- Department of Nephropathology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Gunther Zahner
- Department of Medicine, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
| | - Mario Schiffer
- Department of Nephrology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| |
Collapse
|
|
48
|
Zhao B, Zhang X, Zhang Y, Lu Y, Zhang W, Lu S, Fu Y, Zhou Y, Zhang J, Zhang J. Human Exosomes Accelerate Cutaneous Wound Healing by Promoting Collagen Synthesis in a Diabetic Mice Model. Stem Cells Dev 2021; 30:922-933. [PMID: 34167333 DOI: 10.1089/scd.2021.0100] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Chronic wounds including diabetic foot ulcers are clinical emergencies that need careful management. Exosomes from human adipose-derived mesenchymal stem cells (hADSCs-Ex) are a new promising cell-free therapy for the regeneration of dermal wounds. We established a delayed wound healing model using diabetic female mice. A 1.5 cm2 full-thickness cutaneous wound was made ventrally in 6-week-old db/db mice. After treatment with phosphate-buffered saline, recombinant human epidermal growth factor, hADSCs-CM, or hADSCs-Ex three times a day for 2 weeks, we measured wound healing closure rates and performed histological analysis. Human dermal fibroblasts (WS1) were evaluated by PKH26-Exo co-localization test, CCK-8 test, cell scratch test, and the transwell test, while the expression of matrix metalloproteinase-1 (MMP1), MMP3, Collagen I, and Collagen III were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Wound closure and re-epithelialization were accelerated by hADSCs-Ex. Besides, hADSCs-Ex enhanced skin collagen production, angiogenesis, cell proliferation, inhibited apoptosis, promoted skin barrier function repair, and reduced inflammation in skin lesions. Furthermore, negative regulation of MMP1 and MMP3 enhanced collagen synthesis wound healing-promoting effects of hADSCs-Ex. hADSCs-Ex treatment for diabetic wounds provided a novel cell-free therapeutic strategy.
Collapse
Affiliation(s)
- Bo Zhao
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology Tongji University, Shanghai, People's Republic of China
| | - Xingliao Zhang
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Stem Cell Translational Research Center of Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, People's Republic of China
| | - Yuanlin Zhang
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Stem Cell Translational Research Center of Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, People's Republic of China
| | - Yijun Lu
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Stem Cell Translational Research Center of Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, People's Republic of China
| | - Wanting Zhang
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology Tongji University, Shanghai, People's Republic of China
| | - Shoutao Lu
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Stem Cell Translational Research Center of Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, People's Republic of China
| | - Yu Fu
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology Tongji University, Shanghai, People's Republic of China
| | - Yang Zhou
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Stem Cell Translational Research Center of Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, People's Republic of China
| | - Jun Zhang
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Stem Cell Translational Research Center of Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, People's Republic of China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, People's Republic of China
| | - Jing Zhang
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology Tongji University, Shanghai, People's Republic of China.,Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Stem Cell Translational Research Center of Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, People's Republic of China
| |
Collapse
|
|
49
|
Saccharin and Sucralose Protect the Glomerular Microvasculature In Vitro against VEGF-Induced Permeability. Nutrients 2021; 13:nu13082746. [PMID: 34444906 PMCID: PMC8401733 DOI: 10.3390/nu13082746] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 08/02/2021] [Accepted: 08/06/2021] [Indexed: 12/13/2022] Open
Abstract
Diabetic kidney disease (DKD) has become a global health concern, with about 40% of people living with type 1 and type 2 diabetes mellitus developing DKD. Upregulation of vascular endothelial growth factor (VEGF) in the kidney is a significant pathology of DKD associated with increased glomerular vascular permeability. To date, however, current anti-VEGF therapies have demonstrated limited success in treating DKD. Recent studies have shown that artificial sweeteners exhibit anti-VEGF potential. The aim of this study was therefore to assess the effects of aspartame, saccharin, and sucralose on VEGF-induced leak using an in vitro model of the glomerular endothelium. Saccharin and sucralose but not aspartame protected against VEGF-induced permeability. Whilst the sweeteners had no effect on traditional VEGF signalling, GC-MS analysis demonstrated that the sweetener sucralose was not able to enter the glomerular endothelial cell to exert the protective effect. Chemical and molecular inhibition studies demonstrated that sweetener-mediated protection of the glomerular endothelium against VEGF is dependent on the sweet taste receptor, T1R3. These studies demonstrate the potential for sweeteners to exert a protective effect against VEGF-induced increased permeability to maintain a healthy endothelium and protect against vascular leak in the glomerulus in settings of DKD.
Collapse
|
|
50
|
Steele AR, Tymko MM, Meah VL, Simpson LL, Gasho C, Dawkins TG, Williams AM, Villafuerte FC, Vizcardo-Galindo GA, Figueroa-Mujíca RJ, Ainslie PN, Stembridge M, Moore JP, Steinback CD. Global REACH 2018: Volume regulation in high-altitude Andeans with and without chronic mountain sickness. Am J Physiol Regul Integr Comp Physiol 2021; 321:R504-R512. [PMID: 34346722 DOI: 10.1152/ajpregu.00102.2021] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The high-altitude maladaptation syndrome known as chronic mountain sickness (CMS) is characterized by polycythemia and is associated with proteinuria despite unaltered glomerular filtration rate. However, it remains unclear if indigenous highlanders with CMS have altered volume regulatory hormones. We assessed N-terminal pro-B-type natriuretic peptide (NT pro-BNP), plasma aldosterone concentration, plasma renin activity, kidney function (urinary microalbumin, glomerular filtration rate), blood volume, and estimated pulmonary artery systolic pressure (ePASP), in Andean males without (n=14; age=39±11) and with (n=10; age=40±12) CMS at 4330 meters (Cerro de Pasco, Peru). Plasma renin activity (non-CMS: 15.8±7.9 vs. CMS: 8.7±5.4 ng/ml; p=0.025) and plasma aldosterone concentration (non-CMS: 77.5±35.5 vs. CMS: 54.2±28.9 pg/ml; p=0.018) were lower in highlanders with CMS compared to non-CMS, while NT pro-BNP was not different between groups (non-CMS: 1394.9±214.3 vs. CMS: 1451.1±327.8 pg/ml; p=0.15). Highlanders had similar total blood volume (non-CMS: 90±15 vs. CMS: 103±18 ml • kg-1; p=0.071), but Andeans with CMS had greater total red blood cell volume (non-CMS: 46±10 vs. CMS 66±14 ml • kg-1; p<0.01) and smaller plasma volume (non-CMS 43±7 vs. CMS 35±5 ml • kg-1; p=0.03) compared to non-CMS. There were no differences in ePASP between groups (non-CMS 32±9 vs. CMS 31±8 mmHg; p=0.6). A negative correlation was found between plasma renin activity and glomerular filtration rate in both groups (group: r=-0.66; p<0.01; non-CMS: r=-0.60; p=0.022; CMS: r=-0.63; p=0.049). A smaller plasma volume in Andeans with CMS may indicate an additional CMS maladaptation to high-altitude, causing potentially greater polycythemia and clinical symptoms.
Collapse
Affiliation(s)
- Andrew R Steele
- Neurovascular Health Lab, Faculty of Kinesiology, Sport, and Recreation, University of Alberta, Canada
| | - Michael M Tymko
- Neurovascular Health Lab, Faculty of Kinesiology, Sport, and Recreation, University of Alberta, Canada
| | - Victoria L Meah
- Neurovascular Health Lab, Faculty of Kinesiology, Sport, and Recreation, University of Alberta, Canada.,Women and Children's Health Research Institute, University of Alberta, Canada.,Alberta Diabetes Institute, University of Alberta, Canada
| | - Lydia L Simpson
- Department of Sport Science, Division of Physiology, University of Innsbruck, Austria
| | - Christopher Gasho
- Division of Pulmonary and Critical Care, School of Medicine, Loma Linda University, Loma Linda, CA, United States
| | - Tony G Dawkins
- Cardiff School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff, UK
| | - Alexandra Mackenzie Williams
- Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Canada.,International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, Canada
| | - Francisco C Villafuerte
- Department of Biological and Physiological Sciences, Universidad Peruana Cayetano Heredia, Lima, Peru
| | | | - Rómulo J Figueroa-Mujíca
- Department of Biological and Physiological Sciences, Universidad Peruana Cayetano Heredia, Lima, Peru
| | - Philip N Ainslie
- Centre for Heart, Lung, and Vascular Health, University of British Columbia Okanagan, Kelowna, Canada
| | - Mike Stembridge
- Cardiff School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff, UK
| | - Jonathan P Moore
- Extremes Research Group, School of Sport, Health and Exercise Sciences, Bangor University, Bangor, United Kingdom
| | - Craig D Steinback
- Neurovascular Health Lab, Faculty of Kinesiology, Sport, and Recreation, University of Alberta, Canada.,Women and Children's Health Research Institute, University of Alberta, Canada.,Alberta Diabetes Institute, University of Alberta, Canada.,Neuroscience and Mental Health Institute, University of Alberta, Canada
| |
Collapse
|