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Rogacka D, Rachubik P, Typiak M, Kulesza T, Audzeyenka I, Saleem MA, Sikora H, Gruba N, Wysocka M, Lesner A, Piwkowska A. Involvement of ADAM17-Klotho Crosstalk in High Glucose-Induced Alterations of Podocyte Function. Int J Mol Sci 2025; 26:731. [PMID: 39859443 PMCID: PMC11765903 DOI: 10.3390/ijms26020731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/09/2025] [Accepted: 01/15/2025] [Indexed: 01/27/2025] Open
Abstract
Microalbuminuria is the earliest clinical abnormality in diabetic kidney disease. High glucose (HG) concentrations are associated with the induction of oxidative stress in podocytes, leading to disruption of the glomerular filtration barrier. Our recent study revealed a significant decrease in the membrane-bound fraction of Klotho in podocytes that were cultured under HG conditions. Given that disintegrin and metalloproteinase 17 (ADAM17) is responsible for the shedding of Klotho from the cell membrane, the present study investigated the impact of HG on the interplay between ADAM17 and Klotho in human podocytes. We demonstrated that ADAM17 protein levels significantly increased in urine, renal tissue, and glomeruli from diabetic rats, with a concomitant increase in glomerular albumin permeability. High glucose increased ADAM17 extracellular activity, NADPH oxidase activity, and albumin permeability in podocytes. These effects were reversed after treatment with ADAM17 inhibitor, in cells with downregulated ADAM17 expression, or after the addition of Klotho. Additionally, elevations of extracellular ADAM17 activity were observed in podocytes with the downregulation of Klotho expression. Our data indicate a novel mechanism whereby hyperglycemia deteriorates podocyte function via ADAM17 activation. We also demonstrated the ability of Klotho to protect podocyte function under hyperglycemic conditions in an ADAM17-dependent manner.
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Affiliation(s)
- Dorota Rogacka
- Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 80-308 Gdansk, Poland; (P.R.); (T.K.); (I.A.); (A.P.)
| | - Patrycja Rachubik
- Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 80-308 Gdansk, Poland; (P.R.); (T.K.); (I.A.); (A.P.)
| | - Marlena Typiak
- Department of General and Medical Biochemistry, Faculty of Biology, University of Gdansk, 80-309 Gdansk, Poland;
| | - Tomasz Kulesza
- Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 80-308 Gdansk, Poland; (P.R.); (T.K.); (I.A.); (A.P.)
- Laboratory of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, 80-210 Gdansk, Poland
| | - Irena Audzeyenka
- Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 80-308 Gdansk, Poland; (P.R.); (T.K.); (I.A.); (A.P.)
| | - Moin A. Saleem
- Bristol Renal, University of Bristol, Dorothy Hodgkin Building, Bristol BS1 3NY, UK;
| | - Honorata Sikora
- Department of Biomedical Chemistry, Faculty of Chemistry, University of Gdansk, 80-308 Gdansk, Poland; (H.S.); (M.W.)
| | - Natalia Gruba
- Department of Environmental Technology, Faculty of Chemistry, University of Gdansk, 80-308 Gdansk, Poland; (N.G.); (A.L.)
| | - Magdalena Wysocka
- Department of Biomedical Chemistry, Faculty of Chemistry, University of Gdansk, 80-308 Gdansk, Poland; (H.S.); (M.W.)
| | - Adam Lesner
- Department of Environmental Technology, Faculty of Chemistry, University of Gdansk, 80-308 Gdansk, Poland; (N.G.); (A.L.)
| | - Agnieszka Piwkowska
- Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 80-308 Gdansk, Poland; (P.R.); (T.K.); (I.A.); (A.P.)
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Jia M, Han S, Wang Y. Systemic immunoinflammatory indexes in albuminuric adults are negatively associated with α-klotho: evidence from NHANES 2007-2016. Ren Fail 2024; 46:2385059. [PMID: 39135529 PMCID: PMC11328598 DOI: 10.1080/0886022x.2024.2385059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 05/16/2024] [Accepted: 07/22/2024] [Indexed: 08/18/2024] Open
Abstract
BACKGROUND Systemic Immune-Inflammation Index (SII) is a novel inflammatory biomarker closely associated with the inflammatory response and chronic kidney disease. Klotho is implicated as a pathogenic factor in the progression of kidney disease, and supplementation of Klotho may delay the progression of chronic kidney disease by inhibiting the inflammatory response. Our aim is to investigate the potential relationship between SII and Klotho in adult patients in the United States and explore the differences in the populations with and without albuminuria. METHODS We conducted a cross-sectional study recruiting adult participants with complete data on SII, Klotho, and urine albumin-to-creatinine ratio (ACR) from the National Health and Nutrition Examination Survey from 2007 to 2016. SII was calculated as platelet count × neutrophil count/lymphocyte count, with abnormal elevation defined as values exceeding 330 × 10^9/L. Albuminuria was defined as ACR >30 mg/g. Weighted multivariable regression analysis and subgroup analysis were employed to explore the independent relationship between SII and Klotho. RESULTS Our study included a total of 10,592 individuals. In all populations, non-albuminuria population, and proteinuria population with ACR ≥ 30, participants with abnormally elevated SII levels, as compared to those with SII less than 330 × 10^9/L, showed a negative correlation between elevated SII levels and increased Klotho, which persisted after adjusting for covariates. CONCLUSIONS There is a negative correlation between SII and Klotho in adult patients in the United States. This finding complements previous research but requires further analysis through large prospective studies.
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Affiliation(s)
- Meng Jia
- Department of Nephrology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shisheng Han
- Department of Nephrology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yi Wang
- Department of Nephrology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Li Z, Wu N, Wang J, Yue Y, Geng L, Zhang Q. Low molecular weight fucoidan restores diabetic endothelial glycocalyx by targeting neuraminidase2: A new therapy target in glycocalyx shedding. Br J Pharmacol 2024; 181:1404-1420. [PMID: 37994102 DOI: 10.1111/bph.16288] [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: 04/29/2023] [Revised: 09/16/2023] [Accepted: 11/13/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND AND PURPOSE Diabetic vascular complication is a leading cause of disability and mortality in diabetes patients. Low molecular weight fucoidan (LMWF) is a promising drug candidate for vascular complications. Glycocalyx injury predates the occurrence of diabetes vascular complications. Protecting glycocalyx from degradation relieves diabetic vascular complications. LMWF has the potential to protect the diabetes endothelial glycocalyx from shedding. EXPERIMENTAL APPROACH The protective effect of LMWF on diabetic glycocalyx damage was investigated in db/db mice and Human Umbilical Vein Endothelial Cells (HUVEC) through transmission electron microscopy and WGA labelling. The effect of LMWF on glycocalyx degrading enzymes expression was investigated. Neuraminidase2 (NEU2) overexpression/knockdown was performed in HUVECs to verify the important role of NEU2 in glycocalyx homeostasis. The interaction between NEU2 and LMWF was detected by ELISA and surface plasmon resonance analysis (SPR). KEY RESULTS LMWF normalizes blood indexes including insulin, triglyceride, uric acid and reduces diabetes complications adverse events. LMWF alleviates diabetic endothelial glycocalyx damage in db/db mice kidney/aorta and high concentration glucose treated HUVECs. NEU2 is up-regulated in db/db mice and HUVECs with high concentration glucose. Overexpression/knockdown NEU2 results in glycocalyx shedding in HUVEC. Down-regulation and interaction of LMWF with NEU2 is a new therapy target in glycocalyx homeostasis. NEU2 was positively correlated with phosphorylated IR-β. CONCLUSION AND IMPLICATIONS NEU2 is an effective target for glycocalyx homeostasis and LMWF is a promising drug to alleviate vascular complications in diabetes by protecting endothelial glycocalyx.
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Affiliation(s)
- Zhi Li
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China
- Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China
- Laboratory for Marine Biology and Biotechnology, National Laboratory for Marine Science and Technology (Qingdao), Qingdao, China
- Laboratory for Marine Drugs and Biological Products, National Laboratory for Marine Science and Technology (Qingdao), Qingdao, China
| | - Ning Wu
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China
- Laboratory for Marine Drugs and Biological Products, National Laboratory for Marine Science and Technology (Qingdao), Qingdao, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jing Wang
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China
- Laboratory for Marine Biology and Biotechnology, National Laboratory for Marine Science and Technology (Qingdao), Qingdao, China
| | - Yang Yue
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China
- Laboratory for Marine Biology and Biotechnology, National Laboratory for Marine Science and Technology (Qingdao), Qingdao, China
| | - Lihua Geng
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China
- Laboratory for Marine Biology and Biotechnology, National Laboratory for Marine Science and Technology (Qingdao), Qingdao, China
| | - Quanbin Zhang
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China
- Laboratory for Marine Biology and Biotechnology, National Laboratory for Marine Science and Technology (Qingdao), Qingdao, China
- Laboratory for Marine Drugs and Biological Products, National Laboratory for Marine Science and Technology (Qingdao), Qingdao, China
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Yu H, Song YY, Li XH. Early diabetic kidney disease: Focus on the glycocalyx. World J Diabetes 2023; 14:460-480. [PMID: 37273258 PMCID: PMC10236994 DOI: 10.4239/wjd.v14.i5.460] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 03/10/2023] [Accepted: 04/12/2023] [Indexed: 05/15/2023] Open
Abstract
The incidence of diabetic kidney disease (DKD) is sharply increasing worldwide. Microalbuminuria is the primary clinical marker used to identify DKD, and its initiating step in diabetes is glomerular endothelial cell dysfunction, particularly glycocalyx impairment. The glycocalyx found on the surface of glomerular endothelial cells, is a dynamic hydrated layer structure composed of pro-teoglycans, glycoproteins, and some adsorbed soluble components. It reinforces the negative charge barrier, transduces the shear stress, and mediates the interaction of blood corpuscles and podocytes with endothelial cells. In the high-glucose environment of diabetes, excessive reactive oxygen species and proinflammatory cytokines can damage the endothelial glycocalyx (EG) both directly and indirectly, which induces the production of microalbuminuria. Further research is required to elucidate the role of the podocyte glycocalyx, which may, together with endothelial cells, form a line of defense against albumin filtration. Interestingly, recent research has confirmed that the negative charge barrier function of the glycocalyx found in the glomerular basement membrane and its repulsion effect on albumin is limited. Therefore, to improve the early diagnosis and treatment of DKD, the potential mechanisms of EG degradation must be analyzed and more responsive and controllable targets must be explored. The content of this review will provide insights for future research.
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Affiliation(s)
- Hui Yu
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Yi-Yun Song
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Xian-Hua Li
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
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Soluble Klotho protects against glomerular injury through regulation of ER stress response. Commun Biol 2023; 6:208. [PMID: 36813870 PMCID: PMC9947099 DOI: 10.1038/s42003-023-04563-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 02/07/2023] [Indexed: 02/24/2023] Open
Abstract
αKlotho (Klotho) has well established renoprotective effects; however, the molecular pathways mediating its glomerular protection remain incompletely understood. Recent studies have reported that Klotho is expressed in podocytes and protects glomeruli through auto- and paracrine effects. Here, we examined renal expression of Klotho in detail and explored its protective effects in podocyte-specific Klotho knockout mice, and by overexpressing human Klotho in podocytes and hepatocytes. We demonstrate that Klotho is not significantly expressed in podocytes, and transgenic mice with either a targeted deletion or overexpression of Klotho in podocytes lack a glomerular phenotype and have no altered susceptibility to glomerular injury. In contrast, mice with hepatocyte-specific overexpression of Klotho have high circulating levels of soluble Klotho, and when challenged with nephrotoxic serum have less albuminuria and less severe kidney injury compared to wildtype mice. RNA-seq analysis suggests an adaptive response to increased endoplasmic reticulum stress as a putative mechanism of action. To evaluate the clinical relevance of our findings, the results were validated in patients with diabetic nephropathy, and in precision cut kidney slices from human nephrectomies. Together, our data reveal that the glomeruloprotective effects of Klotho is mediated via endocrine actions, which increases its therapeutic potential for patients with glomerular diseases.
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Chang K, Li Y, Qin Z, Zhang Z, Wang L, Yang Q, Su B. Association between Serum Soluble α-Klotho and Urinary Albumin Excretion in Middle-Aged and Older US Adults: NHANES 2007-2016. J Clin Med 2023; 12:jcm12020637. [PMID: 36675565 PMCID: PMC9863467 DOI: 10.3390/jcm12020637] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/04/2023] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
(1) Background: Preclinical and clinical studies on the anti-aging effect of α-Klotho are emerging. Urinary albumin excretion (UAE) is a well-known biomarker of kidney injury and generalized damage in the cardiovascular system. However, the potential relationship between α-Klotho and UAE is limited and controversial. This study aimed to quantify this relationship in the general middle-aged and elderly population from the National Health and Nutrition Survey (NHANES) 2007-2016. (2) Methods: Serum α-Klotho was measured by enzyme-linked immunosorbent assay. UAE was assessed by the albumin-to-creatinine ratio (ACR). After adjusting for several confounding variables, the relationship between α-Klotho and ACR was analyzed by weighted multivariable logistic regression, subgroup analysis, and interaction tests. A generalized additive model (GAM) with smooth functions using the two-piecewise linear regression model was used to examine the potential nonlinear relationship between α-Klotho and ACR. (3) Results: Among 13,584 participants aged 40-79 years, we observed an independent and significant negative correlation between α-Klotho and ACR (β = -12.22; 95% CI, -23.91, -0.53, p = 0.0448) by multivariable logistic regression analysis, especially in those with age ≥ 60 years, pulse pressure (PP) ≥ 60 mmHg, hypertension or diabetes. We further discovered the nonlinear relationship between α-Klotho and ACR by GAM, revealing the first negative and then positive correlations with an inflection point of 9.91 pg/mL between α-Klotho and ACR. (4) Conclusions: A dose-response relationship between α-Klotho and ACR was demonstrated, and the negative correlation therein indicated that α-Klotho has potential as a serum marker and prophylactic or therapeutic agent despite its metabolic and effective mechanisms needing to be further explored.
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Affiliation(s)
- Kaixi Chang
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, China
- Med+ Biomaterial Institute of West China Hospital, West China School of Medicine of Sichuan University, Chengdu 610041, China
| | - Yupei Li
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, China
- Med+ Biomaterial Institute of West China Hospital, West China School of Medicine of Sichuan University, Chengdu 610041, China
| | - Zheng Qin
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, China
- Med+ Biomaterial Institute of West China Hospital, West China School of Medicine of Sichuan University, Chengdu 610041, China
| | - Zhuyun Zhang
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, China
- Med+ Biomaterial Institute of West China Hospital, West China School of Medicine of Sichuan University, Chengdu 610041, China
| | - Liya Wang
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, China
- Med+ Biomaterial Institute of West China Hospital, West China School of Medicine of Sichuan University, Chengdu 610041, China
| | - Qinbo Yang
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, China
- Med+ Biomaterial Institute of West China Hospital, West China School of Medicine of Sichuan University, Chengdu 610041, China
| | - Baihai Su
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, China
- Med+ Biomaterial Institute of West China Hospital, West China School of Medicine of Sichuan University, Chengdu 610041, China
- Med-X Center for Materials, Sichuan University, Chengdu 610041, China
- Correspondence:
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Chen X, Tan H, Xu J, Tian Y, Yuan Q, Zuo Y, Chen Q, Hong X, Fu H, Hou FF, Zhou L, Liu Y. Klotho-derived peptide 6 ameliorates diabetic kidney disease by targeting Wnt/β-catenin signaling. Kidney Int 2022; 102:506-520. [PMID: 35644285 DOI: 10.1016/j.kint.2022.04.028] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 04/01/2022] [Accepted: 04/27/2022] [Indexed: 01/02/2023]
Abstract
Diabetic kidney disease (DKD) is one of the most common and devastating complications of diabetic mellitus, and its prevalence is rising worldwide. Klotho, an anti-aging protein, is kidney protective in DKD. However, its large size, prohibitive cost and structural complexity hamper its potential utility in clinics. Here we report that Klotho-derived peptide 6 (KP6) mimics Klotho function and ameliorates DKD. In either an accelerated model of DKD induced by streptozotocin and advanced oxidation protein products in unilateral nephrectomized mice or db/db mice genetically prone to diabetes, chronic infusion of KP6 reversed established proteinuria, attenuated glomerular hypertrophy, mitigated podocyte damage, and ameliorated glomerulosclerosis and interstitial fibrotic lesions, but did not affect serum phosphorus and calcium levels. KP6 inhibited β-catenin activation in vivo and blocked the expression of its downstream target genes in glomerular podocytes and tubular epithelial cells. In vitro, KP6 prevented podocyte injury and inhibited β-catenin activation induced by high glucose without affecting Wnt expression. Co-immunoprecipitation revealed that KP6 bound to Wnt ligands and disrupted the engagement of Wnts with low density lipoprotein receptor-related protein 6, thereby interrupting Wnt/β-catenin signaling. Mutated KP6 with a scrambled amino acid sequence failed to bind Wnts and did not alleviate DKD in db/db mice. Thus, our studies identified KP6 as a novel Klotho-derived peptide that ameliorated DKD by blocking Wnt/β-catenin. Hence, our findings also suggest a new therapeutic strategy for the treatment of patients with DKD.
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Affiliation(s)
- Xiaowen Chen
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Bioland Laboratory, Guangzhou, China
| | - Huishi Tan
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Bioland Laboratory, Guangzhou, China
| | - Jie Xu
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Bioland Laboratory, Guangzhou, China
| | - Yuan Tian
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Bioland Laboratory, Guangzhou, China
| | - Qian Yuan
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Bioland Laboratory, Guangzhou, China
| | - Yangyang Zuo
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Bioland Laboratory, Guangzhou, China
| | - Qiyan Chen
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Bioland Laboratory, Guangzhou, China
| | - Xue Hong
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Bioland Laboratory, Guangzhou, China
| | - Haiyan Fu
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Bioland Laboratory, Guangzhou, China
| | - Fan Fan Hou
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Bioland Laboratory, Guangzhou, China
| | - Lili Zhou
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Bioland Laboratory, Guangzhou, China.
| | - Youhua Liu
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Bioland Laboratory, Guangzhou, China; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
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Peroxisome Proliferator-Activated Receptor Gene Knockout Promotes Podocyte Injury in Diabetic Mice. BIOMED RESEARCH INTERNATIONAL 2022; 2022:9018379. [PMID: 35813229 PMCID: PMC9262558 DOI: 10.1155/2022/9018379] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 05/14/2022] [Indexed: 11/17/2022]
Abstract
Objective. To investigate the effects of peroxisome proliferator-activated receptor (PPARγ) expression on renal podocyte in diabetic mice by conditionally knockout mouse PPARγ gene. Methods. Wild-type C57BL mice and PPARγ gene knockout mice were used as research objects to establish the diabetic mouse model, which was divided into normal control group (NC group), normal glucose PPARγ gene knockout group (NK group), diabetic wild-type group (DM group), and diabetic PPARγ gene knockout group (DK group), with 8 mice in each group. After 16 weeks, the mice were sacrificed for renal tissue collection. Morphological changes of renal tissue were observed by HE and Masson staining, and ultrastructure of renal tissue was observed by transmission electron microscope. Protein expressions of PPARγ, podocin, nephrin, collagen IV, and fibronectin (FN) in renal tissues were detected by immunohistochemistry and Western blot, and mRNA changes of PPARγ, podocin, and nephrin in renal tissues were detected by qRT-PCR. Results. Compared with the NC group, the protein and mRNA expressions of PPARγ, podocin, and nephrin decreased in the kidney tissue of mice in the DM group, while the protein expressions of collagen IV and FN increased. The expression of various proteins in kidney tissues of the DK group was consistent with that of the DM group, and the difference was more obvious. The expression of PPARγ protein and mRNA decreased in the NK group, while the expression of podocin, nephrin protein and mRNA, collagen IV, and FN protein showed no significant difference. Conclusion. In diabetic renal tissue, the loss of PPARγ can aggravate podocellular damage and thus promote the occurrence of diabetic renal fibrosis. Increasing the expression of PPARγ may effectively relieve renal podocyte impairment in diabetic patients, which can be used for the treatment of diabetic nephropathy.
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Xin C, Sun X, Li Z, Gao T. Relationship of Soluble Klotho and Early Stage of Diabetic Nephropathy: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne) 2022; 13:902765. [PMID: 35692408 PMCID: PMC9186104 DOI: 10.3389/fendo.2022.902765] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 04/25/2022] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is a chronic microvascular complication caused by long-term hyperglycemia in patients with diabetes and an important cause of end-stage renal disease. Although some studies have shown that soluble Klotho(sKlotho) levels of patients with DN are lower than those without DN, in the early stage of patients with DN with normal renal function and albuminuria, the change in sKlotho is still controversial. AIM This meta-analysis was conducted to statistically evaluate sKlotho levels in patients with DN. METHODS We searched the following electronic databases: Web of Science, Embase, PubMed, Google Scholar, and China National Knowledge Infrastructure (CNKI). The following search terms were used for the title or abstract: "diabetic kidney disease", "diabetic nephropathy", OR "DN" in combination with "Klotho". The meta-analysis results were presented as standardized mean differences (SMDs) with corresponding 95% confidence intervals (CIs). RESULTS Fourteen articles were included in the meta-analysis. In our meta-analysis, we found that the sKlotho level in patients with DN was significantly lower than that in patients without DN (SMD: -1.52, 95% CI [-2.24, -0.80]), and it was also significantly lower in the early stage of DN (SMD: -1.65, 95% CI [-2.60, -0.70]). CONCLUSIONS This systematic review was the first to evaluate the relationship between sKlotho levels and DN. The sKlotho level was significantly lower in the early stages of DN, indicating that sKlotho might be a new biomarker of DN in the future.
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Affiliation(s)
- Caihong Xin
- Liaoning University of Traditional Chinese Medicine, Shenyang, China
- Department of Endocrinology and Metabolism, Fourth People’s Hospital of Shenyang, Shenyang, China
| | - Xin Sun
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zheng Li
- Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - Tianshu Gao
- Liaoning University of Traditional Chinese Medicine, Shenyang, China
- *Correspondence: Tianshu Gao,
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Park MY, Le Henaff C, Sitara D. Administration of α-Klotho Does Not Rescue Renal Anemia in Mice. Front Pediatr 2022; 10:924915. [PMID: 35813388 PMCID: PMC9259788 DOI: 10.3389/fped.2022.924915] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 05/27/2022] [Indexed: 12/05/2022] Open
Abstract
Renal anemia is a common complication in chronic kidney disease (CKD), associated with decreased production of erythropoietin (EPO) due to loss of kidney function, and subsequent decreased red blood cell (RBC) production. However, many other factors play a critical role in the development of renal anemia, such as iron deficiency, inflammation, and elevated fibroblast growth factor 23 (FGF23) levels. We previously reported that inhibition of FGF23 signaling rescues anemia in mice with CKD. In the present study we sought to investigate whether α-Klotho deficiency present in CKD also contributes to the development of renal anemia. To address this, we administered α-Klotho to mice with CKD induced by an adenine-rich diet. Mice were sacrificed 24 h after α-Klotho injection, and blood and organs were collected immediately post-mortem. Our data show that α-Klotho administration had no beneficial effect in mice with CKD-associated anemia as it did not increase RBC numbers and hemoglobin levels, and it did not stimulate EPO secretion. Moreover, α-Klotho did not improve iron deficiency and inflammation in CKD as it had no effect on iron levels or inflammatory markers. Interestingly, Klotho supplementation significantly reduced the number of erythroid progenitors in the bone marrow and downregulated renal Epo and Hif2α mRNA in mice fed control diet resulting in reduced circulating EPO levels in these mice. In addition, Klotho significantly decreased intestinal absorption of iron in control mice leading to reduced serum iron and transferrin saturation levels. Our findings demonstrate that α-Klotho does not have a direct role in renal anemia and that FGF23 suppresses erythropoiesis in CKD via a Klotho-independent mechanism. However, in physiological conditions α-Klotho appears to have an inhibitory effect on erythropoiesis and iron regulation.
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Affiliation(s)
- Min Young Park
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, NY, United States
| | - Carole Le Henaff
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, NY, United States
| | - Despina Sitara
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, NY, United States.,Medicine, NYU School of Medicine, New York, NY, United States
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11
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Oishi H, Doi S, Nakashima A, Ike T, Maeoka Y, Sasaki K, Doi T, Masaki T. Klotho overexpression protects against renal aging along with suppression of transforming growth factor-β1 signaling pathways. Am J Physiol Renal Physiol 2021; 321:F799-F811. [PMID: 34779262 DOI: 10.1152/ajprenal.00609.2020] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Klotho is an antiaging protein reported to suppress transforming growth factor-β1 (TGF-β1) signaling. Aging kidneys are characterized by interstitial fibrosis, accumulation of cell cycle-arrested cells, and increased levels of oxidative stress. TGF-β1 signaling is involved in these processes. In this study, we investigated whether klotho overexpression improves these features in the kidneys of aging mice and examined the inhibitory effect of klotho on signaling molecules related to transforming growth of TGF-β1. Klotho transgenic (KLTG) and wild-type (WT) mice were used, and 8-wk-old and 24-mo-old mice were defined as young and aging, respectively. We found that klotho expression was decreased in aging WT mice, but it was maintained in aging KLTG mice. Klotho overexpression improved the survival of 24-mo-old mice. Although the serum Ca2+ level was significantly lower in aging KLTG mice than in aging WT mice, the serum phosphate level did not differ between these mice. Klotho overexpression attenuated the increases in blood pressure, serum blood urea nitrogen level, and serum creatinine level in aging mice. Interstitial fibrosis, accumulation of cell cycle-arrested cells, and oxidative stress did not differ between young KLTG and WT mice, but they were significantly suppressed in aging KLTG mice compared with aging WT mice. Furthermore, the expression of TGF-β1-related signaling molecules was increased in aging WT mice, whereas it was inhibited in aging KLTG mice. These data suggest that klotho overexpression protects against kidney aging along with suppression of TGF-β1 signaling pathways.NEW & NOTEWORTHY Klotho is considered as an antiaging protein, and its overexpression may be a candidate therapy for protection against kidney damage with advanced aging. Although multiple factors are involved in the aging process, we showed that klotho overexpression inhibited interstitial fibrosis, accumulation of cell cycle-arrested cells, and increased levels of oxidative stress in the kidneys of aging mice, suppressing transforming growth factor-β1-related signaling pathways. The present data showed that klotho overexpression protects against age-associated kidney damage.
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Affiliation(s)
- Hiroaki Oishi
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Shigehiro Doi
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Ayumu Nakashima
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.,Department of Stem Cell Biology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takeshi Ike
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Yujiro Maeoka
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Kensuke Sasaki
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Toshiki Doi
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Takao Masaki
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
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12
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Xing L, Fang J, Zhu B, Wang L, Chen J, Wang Y, Huang J, Wang H, Yao X. Astragaloside IV protects against podocyte apoptosis by inhibiting oxidative stress via activating PPARγ-Klotho-FoxO1 axis in diabetic nephropathy. Life Sci 2021; 269:119068. [PMID: 33476631 DOI: 10.1016/j.lfs.2021.119068] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 01/05/2021] [Accepted: 01/13/2021] [Indexed: 01/07/2023]
Abstract
AIMS Podocyte apoptosis plays an important role in the pathogenesis of diabetic nephropathy (DN). Astragaloside IV (AS-IV) has been shown to protect against podocyte apoptosis. Here we aim to investigate the mechanism responsible for the protective effects of AS-IV. MAIN METHODS Diabetic db/db mice and high glucose (HG)-cultured podocytes were treated with AS-IV. Renal function and histopathological changes were measured to evaluate the therapeutic effects of AS-IV against DN. Adenovirus-mediated Klotho overexpression, Klotho siRNA, and PPARγ inhibitor were applied in vitro to investigate the potential mechanism. The expression levels of mRNA and proteins were analyzed by qRT-PCR, western blot or immunofluorescence. Intracellular ROS and mitochondrial superoxide were detected by DHE and MitoSOx Red, respectively. Cell apoptosis was evaluated by TUNEL staining and flow cytometry. KEY FINDINGS AS-IV improved renal function and ameliorated podocyte injury in db/db mice accompanied with enhanced Klotho expression in glomerular podocytes. In vitro, AS-IV inhibited HG-induced podocyte apoptosis and restored HG-inhibited Klotho expression, whereas Klotho knockdown abrogated the anti-apoptosis action of AS-IV. Further study showed that adenovirus-mediated Klotho overexpression enhanced Forkhead transcription factor O1 (FoxO1)-dependent antioxidant activity and attenuated HG-evoked oxidative stress and apoptosis. AS-IV prevented HG-induced FoxO1 inhibition and oxidative stress, whereas Klotho knockdown reversed these effects. Cotreatment with PPARγ inhibitor T0070907 abolished AS-IV-induced Klotho expression and anti-apoptosis action. SIGNIFICANCE These data suggested that AS-IV attenuated podocyte apoptosis presumably by inhibiting oxidative stress via activating PPARγ-Klotho-FoxO1 signaling pathway, thereby ameliorating DN. This study provided new insights into the molecular mechanisms of AS-IV against DN.
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Affiliation(s)
- Lina Xing
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Ji Fang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Bingbing Zhu
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Li Wang
- Laboratory of Renal Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Junliang Chen
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Yunman Wang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Jiebo Huang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Hao Wang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China.
| | - Xingmei Yao
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China.
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Xing L, Guo H, Meng S, Zhu B, Fang J, Huang J, Chen J, Wang Y, Wang L, Yao X, Wang H. Klotho ameliorates diabetic nephropathy by activating Nrf2 signaling pathway in podocytes. Biochem Biophys Res Commun 2020; 534:450-456. [PMID: 33256980 DOI: 10.1016/j.bbrc.2020.11.061] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 11/14/2020] [Indexed: 12/20/2022]
Abstract
Oxidative stress plays a key role in the pathogenesis of diabetic nephropathy (DN). The anti-aging protein Klotho has been demonstrated to have antioxidant capacity. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a central transcription factor regulating antioxidant responses. The present study aimed to explore the effects of Klotho on DN and the underlying mechanisms related to Nrf2. Low glucose (LG) or high glucose (HG) medium-cultured podocytes and diabetic db/db mice were overexpressed with Klotho via adenoviral transfer to evaluate the effects of Klotho on Nrf2 signaling, oxidative stress, podocyte apoptosis, and renal function and histopathology. Klotho overexpression significantly induced the expression and activation of Nrf2 as well as its downstream targets SOD2 and NQO1 in podocytes. Moreover, Klotho overexpression inhibited HG-induced oxidative stress and apoptosis in podocytes. Co-treatment with Nrf2 inhibitor trigonelline prevented Klotho-induced expression of SOD2 and NQO1, and abolished Klotho-conferred antioxidant and anti-apoptotic effects. In db/db mice, Klotho overexpression also activated Nrf2 signaling, and suppressed diabetes-induced oxidative stress and podocyte apoptosis, which were accompanied by improved renal function and decreased glomerulosclerosis. Our data highlight a novel Nrf2-mediated antioxidant mechanism underlying the protective effects of Klotho in podocytes and indicate the therapeutic potential of targeting Klotho to activate Nrf2 in DN.
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Affiliation(s)
- Lina Xing
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Hengjiang Guo
- Department of Anesthesiology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200062, China
| | - Sixuan Meng
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Bingbing Zhu
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Ji Fang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Jiebo Huang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Junliang Chen
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Yunman Wang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Li Wang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Xingmei Yao
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
| | - Hao Wang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
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Kadoya H, Satoh M, Nishi Y, Kondo M, Wada Y, Sogawa Y, Kidokoro K, Nagasu H, Sasaki T, Kashihara N. Klotho is a novel therapeutic target in peritoneal fibrosis via Wnt signaling inhibition. Nephrol Dial Transplant 2020; 35:773-781. [PMID: 32221606 DOI: 10.1093/ndt/gfz298] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 12/06/2019] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Long-term exposure to bioincompatible peritoneal dialysate causes the loss of mesothelial cells and accumulation of matrix proteins, leading to an increase in the thickness of the submesothelial layer, thereby limiting the long-term effectiveness of peritoneal dialysis (PD). However, the detailed molecular mechanisms underlying the process of peritoneal fibrosis have not been clearly elucidated. Wnt/β-catenin signaling pathway activation has been suggested to play a pivotal role in the development of organ fibrosis. Moreover, Klotho protein can regulate Wnt/β-catenin signaling. We examined the role of Klotho protein in reducing peritoneal fibrosis by inhibiting Wnt/β-catenin signaling. METHODS The β-catenin-activated transgenic (BAT) driving expression of nuclear β-galactosidase reporter transgenic (BAT-LacZ) mice, the alpha-Klotho gene under control of human elongation factor 1 alpha promoter [Klotho transgenic (KLTG) and C57BL/6 background] and C57BL/6 mice [wild-type (WT)] were used. The mice received daily intraperitoneal (i.p.) injections of 4.25% glucose with lactate (PD solution) or saline as a control for 4 weeks. Other mice received daily i.p. injections of the same volume of saline (normal control). RESULTS After exposure to PD, Wnt signal activation was observed on the peritoneal mesothelial cells in WT-PD mice. The peritoneal fibrosis was also accelerated in WT-PD mice. The protein expression of β-catenin and Wnt-inducible genes were also remarkably increased in WT-PD mice. On the other hand, KLTG-PD mice attenuated activation of Wnt/β-catenin signaling after exposure to PD and ameliorated the progression of peritoneal fibrosis. CONCLUSIONS Overexpression of Klotho protein protects the peritoneal membrane through attenuation of the Wnt/β-catenin signaling pathway. The availability of recombinant Klotho protein would provide a novel potential therapeutic target in peritoneal fibrosis.
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Affiliation(s)
- Hiroyuki Kadoya
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Minoru Satoh
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Yuko Nishi
- Internal Medicine, Nishi Clinic, Tsuyama, Okayama, Japan
| | - Megumi Kondo
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Yoshihisa Wada
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Yuji Sogawa
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Kengo Kidokoro
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Hajime Nagasu
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Tamaki Sasaki
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Naoki Kashihara
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
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15
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Itano S, Kadoya H, Satoh M, Nakamura T, Murase T, Sasaki T, Kanwar YS, Kashihara N. Non-purine selective xanthine oxidase inhibitor ameliorates glomerular endothelial injury in Ins Akita diabetic mice. Am J Physiol Renal Physiol 2020; 319:F765-F772. [PMID: 32954851 DOI: 10.1152/ajprenal.00236.2020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Endothelial dysfunction represents a predominant early feature of diabetes, rendering patients with diabetes prone to renal complications, e.g., proteinuria. Recent studies have indicated a possible role for xanthine oxidase (XO) in the pathogenesis of vascular dysfunctions associated with diabetes. In the present study, we investigated the contribution of XO activation on the progression of diabetic nephropathy in a mouse model using selective XO inhibitors. Male Ins2Akita heterozygous mice were used with wild-type mice as controls. Akita mice were treated with topiroxostat (Topi) or vehicle for 4 wk. Serum uric acid levels were significantly reduced in Akita + Topi mice compared with Akita + vehicle mice. The Akita + Topi group had a significant reduction in urinary albumin excretion compared with the Akita + vehicle group. Mesangial expansion, glomerular collagen type IV deposition, and glomerular endothelial injury (assessed by lectin staining and transmission electron microscopy) were considerably reduced in the Akita + topi group compared with the Akita + vehicle group. Furthermore, glomerular permeability was significantly higher in the Akita + vehicle group compared with the wild-type group. These changes were reduced with the administration of Topi. We conclude that XO inhibitors preserve glomerular endothelial functions and rescue compromised glomerular permeability, suggesting that XO activation plays a vital role in the pathogenesis of diabetic nephropathy.
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Affiliation(s)
- Seiji Itano
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Hiroyuki Kadoya
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Minoru Satoh
- Department of General Medicine/Nephrology, Kobe Rosai Hospital, Kobe, Hyogo, Japan
| | - Takashi Nakamura
- Pharmacological Study Group, Pharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho, Mie, Japan
| | - Takayo Murase
- Radioisotope and Chemical Analysis Center, Laboratory Management Department, Sanwa Kagaku Kenkyusho, Mie, Japan
| | - Tamaki Sasaki
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Yashpal S Kanwar
- Department of Pathology and Medicine, Northwestern University, Chicago, Illinois, USA
| | - Naoki Kashihara
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
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EGCG Attenuates Renal Damage via Reversing Klotho Hypermethylation in Diabetic db/db Mice and HK-2 Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:6092715. [PMID: 32908633 PMCID: PMC7474393 DOI: 10.1155/2020/6092715] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 06/01/2020] [Accepted: 06/16/2020] [Indexed: 02/06/2023]
Abstract
To explore whether epigallocatechin-3-gallate (EGCG) improves renal damage in diabetic db/db mice and high-glucose- (HG-) induced injury in HK-2 cells by regulating the level of Klotho gene promoter methylation. Western blotting was used to detect the protein expression levels of DNA methyltransferase 1 (DNMT1), DNMT3a, DNMT3b, transforming growth factor-β1 (TGF-β1), α-smooth muscle actin (α-SMA), and Klotho. The methylation level of the Klotho gene promoter was detected by pyrosequencing. Chromatin immunoprecipitation was used to detect the binding of the Klotho gene promoter to DNMT1 and DNMT3a. The expression of oxidative stress markers (reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), and 8-hydroxy-2′-deoxyguanosine (8-OHdG)) and inflammatory cytokines (interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α)) in kidney homogenates was also measured using ELISA. Klotho and DNMT3b protein expression was upregulated, while DNMT1, DNMT3a, TGF-β1, and α-SMA protein expression was downregulated after EGCG treatment. EGCG treatment also reduced the methylation level of the Klotho gene promoter as well as the binding of DNMT3a to the Klotho gene promoter. In addition, EGCG treatment significantly decreased the levels of ROS, MDA, 8-OHdG, IL-1β, IL-6, and TNF-α and increased the levels of CAT and SOD. Under HG conditions, EGCG regulated Klotho gene promoter methylation via DNMT3a and decreased the methylation level of the Klotho gene promoter, thereby upregulating the expression of the Klotho protein to exert its protective effect.
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Guo J, Zheng HJ, Zhang W, Lou W, Xia C, Han XT, Huang WJ, Zhang F, Wang Y, Liu WJ. Accelerated Kidney Aging in Diabetes Mellitus. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:1234059. [PMID: 32774664 PMCID: PMC7407029 DOI: 10.1155/2020/1234059] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 05/25/2020] [Accepted: 06/25/2020] [Indexed: 02/07/2023]
Abstract
With aging, the kidney undergoes inexorable and progressive changes in structural and functional performance. These aging-related alterations are more obvious and serious in diabetes mellitus (DM). Renal accelerated aging under DM conditions is associated with multiple stresses such as accumulation of advanced glycation end products (AGEs), hypertension, oxidative stress, and inflammation. The main hallmarks of cellular senescence in diabetic kidneys include cyclin-dependent kinase inhibitors, telomere shortening, and diabetic nephropathy-associated secretory phenotype. Lysosome-dependent autophagy and antiaging proteins Klotho and Sirt1 play a fundamental role in the accelerated aging of kidneys in DM, among which the autophagy-lysosome system is the convergent mechanism of the multiple antiaging pathways involved in renal aging under DM conditions. Metformin and the inhibitor of sodium-glucose cotransporter 2 are recommended due to their antiaging effects independent of antihyperglycemia, besides angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. Additionally, diet intervention including low protein and low AGEs with antioxidants are suggested for patients with diabetic nephropathy (DN). However, their long-term benefits still need further study. Exploring the interactive relationships among antiaging protein Klotho, Sirt1, and autophagy-lysosome system may provide insight into better satisfying the urgent medical needs of elderly patients with aging-related DN.
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Affiliation(s)
- Jing Guo
- Renal Research Institution; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China
| | - Hui Juan Zheng
- Renal Research Institution; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China
| | - Wenting Zhang
- Renal Research Institution; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China
| | - Wenjiao Lou
- Renal Research Institution; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China
| | - Chenhui Xia
- Renal Research Institution; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China
| | - Xue Ting Han
- Renal Research Institution; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China
| | - Wei Jun Huang
- Renal Research Institution; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China
| | - Fan Zhang
- Renal Research Institution; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China
| | - Yaoxian Wang
- Renal Research Institution; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China
| | - Wei Jing Liu
- Renal Research Institution; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China
- Institute of Nephrology, and Zhanjiang Key Laboratory of Prevention and Management of Chronic Kidney Disease, Guangdong Medical University, No. 57th South Renmin Road, Zhanjiang, Guangdong 524001, China
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Tarhani F, Heidari G, Nezami A. Evaluation of α-klotho level in insulin dependent diabetes mellitus (IDDM) children. J Pediatr Endocrinol Metab 2020; 33:761-765. [PMID: 32469333 DOI: 10.1515/jpem-2019-0591] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Accepted: 03/10/2020] [Indexed: 01/24/2023]
Abstract
Objectives Reduced levels of α-Klotho is associated with the pathogenesis of various diseases including diabetes. In type I diabetes, decrease in Klotho leads to apoptosis of β-cells of pancreases. The aim of this study was to evaluate the levels of α-Klotho in type I diabetic pediatric patients. Methods In this cross-sectional single centered study, 46 patients presenting type I diabetes mellitus (case group) and 78 control group under the age of 12, referred to our clinic were included in our study. Serum levels of soluble Klotho were measured by sandwich ELISA in case and control groups. Statistical analysis was conducted for the data recorded via questionnaire. Results Mean age of the patients in the case and control group was 7.65 ± 3.09 and 7 ± 2.37, respectively. Type I diabetes patients had a significant reduction in the levels of serum Klotho, as compared to controls (p<0.001). However, gender and age-based comparison between patient and control group was not significant. Conclusions This study reports a significant decrease in the serum levels of α-Klotho in type 1 diabetic patients. Low levels of Klotho can be associated with diabetic nephropathy and other comorbidities in these patients.
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Affiliation(s)
- Fariba Tarhani
- Department of Pediatric, Faculty of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Ghobad Heidari
- Department of Pediatric, Faculty of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Alireza Nezami
- Department of Pediatric, Faculty of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
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Long noncoding RNA NEAT1 is involved in the protective effect of Klotho on renal tubular epithelial cells in diabetic kidney disease through the ERK1/2 signaling pathway. Exp Mol Med 2020; 52:266-280. [PMID: 32054986 PMCID: PMC7062691 DOI: 10.1038/s12276-020-0381-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 12/10/2019] [Accepted: 01/01/2020] [Indexed: 11/16/2022] Open
Abstract
Klotho, an antiaging protein, has been shown to play a protective role in renal tubular epithelial-mesenchymal transition (EMT) during the development of diabetic kidney disease (DKD). Long noncoding RNAs (lncRNAs) participate in the progression of EMT in many diseases. However, the effect of Klotho on lncRNAs during the development of DKD is still unknown. In this study, we found that Klotho overexpression in high-fat diet (HFD)- and streptozotocin (STZ)-induced DKD mice significantly inhibited the expression of lncRNA nuclear-enriched abundant transcript 1 (Neat1). We demonstrated that NEAT1 was significantly upregulated in both bovine serum albumin (BSA)-stimulated HK2 cells and mice with HFD- and STZ-induced diabetes. In addition, we observed that Klotho displays colocalization with NEAT1. Furthermore, overexpression of Klotho can inhibit the high expression of NEAT1 in BSA-stimulated HK2 cells, while silencing Klotho can further upregulate the expression of NEAT1. Silencing NEAT1 in HK2 cells resulted in inhibition of the EMT-related markers alpha smooth muscle actin (α-SMA) and vimentin (VIM) and the renal fibrosis-related markers transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF). The effect of NEAT1 on DKD was partly mediated by regulation of the ERK1/2 signaling pathway. Finally, we found that silencing NEAT1 can reverse the activation of EMT and fibrosis caused by Klotho silencing in a manner dependent on the ERK1/2 signaling pathway. These findings reveal a new regulatory pathway by which Klotho regulates ERK1/2 signaling via NEAT1 to protect against EMT and renal fibrosis, suggesting that NEAT1 is a potential therapeutic target for DKD. An anti-ageing protein called Klotho helps protect against kidney failure in mice and human cells by silencing a long non-coding RNA molecule. The regulatory RNA involved, known as NEAT1, promotes cellular transformations associated with the disease process. A team led by Yao-Ming Xue from Southern Medical University in Guangdong, China, showed that levels of NEAT1 are elevated in mouse models of diabetic kidney disease and in injured human kidney calls. The identification of NEAT1 in kidney disease thus provides a novel therapeutic target. After demonstrating that Klotho and NEAT1 interact directly with each other in cells, they experimentally boosted Klotho expression and observed suppressed levels of NEAT1. As a consequence, the cells displayed lower levels of the proteins linked to the progressive deposition of fibrosis in the kidneys.
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Wang Q, Ren D, Li Y, Xu G. Klotho attenuates diabetic nephropathy in db/db mice and ameliorates high glucose-induced injury of human renal glomerular endothelial cells. Cell Cycle 2019; 18:696-707. [PMID: 30784349 DOI: 10.1080/15384101.2019.1580495] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Glomerular endothelial cell injury plays an important role in the development and progression of diabetic nephropathy (DN). The expression and function of klotho in glomerular endothelial cells remain unclear. Thus, this study aimed to investigate the expression and the functional role of klotho in DN progression in mice and in high glucose (HG)-induced cell injury of human renal glomerular endothelial cells (HRGECs) and the underlying mechanism. In this study, HRGECs were cultured with media containing HG to induce endothelial cell injury and db/db mice were used as DN model mice. Klotho was overexpressed or knocked down in HRECs to evaluate its role in HG-induced HRGECs injury. klotho-overexpressing adenovirus (rAAV-klotho) was injected into db/db mice via the tail vein to further validate the protective effect of klotho in DN. Decreased klotho expression was observed in DN patients, DN mice, and HG-exposed HRGECs. Furthermore, klotho overexpression significantly abolished the HG-induced HRGECs injury and activation of Wnt/β-catenin pathway and RAAS. In contrast, klotho knockdown exerted the opposite effects. Moreover, klotho attenuated diabetic nephropathy in db/db mice, which was also associated with inhibition of the Wnt/β-catenin pathway and RAAS. In conclusion, klotho attenuates DN in db/db mice and ameliorates HG-induced injury of HRGECs.
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Affiliation(s)
- Qi Wang
- a Department of Nephrology , the Second Affiliated Hospital of Nanchang University , Nanchang , China
| | - Daijin Ren
- a Department of Nephrology , the Second Affiliated Hospital of Nanchang University , Nanchang , China
| | - Yebei Li
- a Department of Nephrology , the Second Affiliated Hospital of Nanchang University , Nanchang , China
| | - Gaosi Xu
- a Department of Nephrology , the Second Affiliated Hospital of Nanchang University , Nanchang , China
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21
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Takenaka T, Kobori H, Miyazaki T, Suzuki H, Nishiyama A, Ishii N, Yamashita M, Hayashi M. Klotho protein supplementation reduces blood pressure and renal hypertrophy in db/db mice, a model of type 2 diabetes. Acta Physiol (Oxf) 2019; 225:e13190. [PMID: 30251773 DOI: 10.1111/apha.13190] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 09/19/2018] [Accepted: 09/19/2018] [Indexed: 12/18/2022]
Abstract
AIMS Klotho interacts with various membrane proteins, such as receptors for transforming growth factor (TGF)-β and insulin-like growth factor (IGF), to alter their function. Renal expression of klotho is diminished in diabetes. The present study examined whether exogenous klotho protein supplementation ameliorates kidney injury and renin-angiotensin system (RAS) in db/db mice. METHODS We investigated the effects of klotho supplementation on diabetic kidney injury and RAS. Recombinant human klotho protein (10 μg/kg/d) was administered to db/db mice daily. RESULTS Klotho protein supplementation reduced kidney weight, systolic blood pressure (SBP), albuminuria, glomerular filtration rate, and 8-epi-prostaglandin F2α excretion without affecting body weight. Although klotho supplementation did not alter glycated albumin, it reduced renal angiotensin II levels associated with reduced renal expression of angiotensinogen. Klotho supplementation improved renal expression of superoxide dismutase (SOD), and endogenous renal expression of klotho. Klotho supplementation reduced the levels of hypoxia-inducible factor, phosphorylated Akt, and phosphorylated mTOR and decreased the renal expression of TGF-β, tumour necrosis factor (TNF), and fibronectin. CONCLUSIONS These data indicate that klotho supplementation reduces blood pressure and albuminuria along with ameliorating renal RAS activation in db/db mice. Furthermore, these results suggest that klotho inhibits IGF signalling, induces SOD expression to reduce oxidative stress, and suppresses Akt-mTOR signalling to inhibit abnormal kidney growth. Collectively, the results suggest that klotho inhibits TGF-β and TNF signalling, resulting in a decline in renal fibrosis.
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Affiliation(s)
- Tsuneo Takenaka
- International University of Health and Welfare; Minato Japan
| | - Hiroyuki Kobori
- International University of Health and Welfare; Minato Japan
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22
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Transforming growth factor β (TGFβ) and related molecules in chronic kidney disease (CKD). Clin Sci (Lond) 2019; 133:287-313. [DOI: 10.1042/cs20180438] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 12/04/2018] [Accepted: 01/07/2019] [Indexed: 02/07/2023]
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23
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Eltablawy N, Ashour H, Rashed LA, Hamza WM. Vitamin D protection from rat diabetic nephropathy is partly mediated through Klotho expression and renin-angiotensin inhibition. Arch Physiol Biochem 2018; 124:461-467. [PMID: 29308676 DOI: 10.1080/13813455.2018.1423624] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE We hypothesised that vitamin D has a beneficial renal protective effect from diabetic nephropathy (DN). METHODS Four rat groups were included: normal control (control), type 2 diabetes for eight weeks (DM), treated group with angiotensin receptor blocker losartan (DM + L), and vitamin D-treated group started from the onset of diabetes (DM + Vit D). RESULTS In the both treated groups, we found a significant (p < .05) reduction in the renal pro-inflammatory and profibrotic markers induced by diabetes. Vitamin D caused more reduction in monocyte chemoattractant protein-1 (MCP-1), transforming growth factor (TGFβ-1), and renin-angiotensin levels that gave better kidney function compared to the DM + L group. CONCLUSION Vitamin D may have a valuable role in the renal protective effect from DN, this may occur via expression of its VDR, Klotho and blocking renin-angiotensin activation, so vitamin D should be considered as a target in renal prophylactic measures against DN.
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Affiliation(s)
- Nashwa Eltablawy
- a Department of Medical Physiology , Kasr Alainy, Faculty of Medicine, Cairo University , Cairo , Egypt
| | - Hend Ashour
- a Department of Medical Physiology , Kasr Alainy, Faculty of Medicine, Cairo University , Cairo , Egypt
| | - Laila Ahmed Rashed
- b Department of Medical Biochemistry , Kasr Alainy, Faculty of Medicine, Cairo University , Cairo , Egypt
| | - Wael Mostafa Hamza
- c Department of Pathology (Nephropathology) , Kasr Alainy, Faculty of Medicine, Cairo University , Cairo , Egypt
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24
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Dogné S, Flamion B, Caron N. Endothelial Glycocalyx as a Shield Against Diabetic Vascular Complications: Involvement of Hyaluronan and Hyaluronidases. Arterioscler Thromb Vasc Biol 2018; 38:1427-1439. [PMID: 29880486 PMCID: PMC6039403 DOI: 10.1161/atvbaha.118.310839] [Citation(s) in RCA: 119] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 05/21/2018] [Indexed: 12/24/2022]
Abstract
The endothelial glycocalyx (EG), which covers the apical surface of the endothelial cells and floats into the lumen of the vessels, is a key player in vascular integrity and cardiovascular homeostasis. The EG is composed of PGs (proteoglycans), glycoproteins, glycolipids, and glycosaminoglycans, in particular hyaluronan (HA). HA seems to be implicated in most of the functions described for EG such as creating a space between blood and the endothelium, controlling vessel permeability, restricting leukocyte and platelet adhesion, and allowing an appropriate endothelial response to flow variation through mechanosensing. The amount of HA in the EG may be regulated by HYAL (hyaluronidase) 1, the most active somatic hyaluronidase. HYAL1 seems enriched in endothelial cells through endocytosis from the bloodstream. The role of the other main somatic hyaluronidase, HYAL2, in the EG is uncertain. Damage to the EG, accompanied by shedding of one or more of its components, is an early sign of various pathologies including diabetes mellitus. Shedding increases the blood or plasma concentration of several EG components, such as HA, heparan sulfate, and syndecan. The plasma levels of these molecules can then be used as sensitive markers of EG degradation. This has been shown in type 1 and type 2 diabetic patients. Recent experimental studies suggest that preserving the size and amount of EG HA in the face of diabetic insults could be a useful novel therapeutic strategy to slow diabetic complications. One way to achieve this goal, as suggested by a murine model of HYAL1 deficiency, may be to inhibit the function of HYAL1. The same approach may succeed in other pathological situations involving endothelial dysfunction and EG damage.
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Affiliation(s)
- Sophie Dogné
- From the Molecular Physiology Research Unit-URPhyM, Namur Research Institute for Life Sciences (NARILIS), University of Namur (Unamur), Belgium.
| | - Bruno Flamion
- From the Molecular Physiology Research Unit-URPhyM, Namur Research Institute for Life Sciences (NARILIS), University of Namur (Unamur), Belgium
| | - Nathalie Caron
- From the Molecular Physiology Research Unit-URPhyM, Namur Research Institute for Life Sciences (NARILIS), University of Namur (Unamur), Belgium
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25
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Fountoulakis N, Maltese G, Gnudi L, Karalliedde J. Reduced Levels of Anti-Ageing Hormone Klotho Predict Renal Function Decline in Type 2 Diabetes. J Clin Endocrinol Metab 2018; 103:2026-2032. [PMID: 29509906 DOI: 10.1210/jc.2018-00004] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2018] [Accepted: 02/26/2018] [Indexed: 02/09/2023]
Abstract
CONTEXT AND OBJECTIVE Soluble Klotho (sKlotho) is a circulating hormone with cardiovascular-renal protective effects. Whether sKlotho predicts estimated glomerular filtration rate (eGFR) decline in patients with type 2 diabetes mellitus (T2DM) with relatively preserved renal function is unknown. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS Single-center observational follow-up study of 101 patients with T2DM and eGFR >45 mL/min [91% on renin angiotensin system (RAS) blockade] followed for a median of 9 years (range, 2 to 13 years). MAIN OUTCOME Primary outcome was a >50% decline in eGFR. sKlotho, serum phosphorus, serum calcium, and fibroblast growth factor-23 levels were measured from stored samples collected at baseline. Patients were followed up with standardized clinical and biochemical measurements. RESULTS Patients with residual microalbuminuria (MA) despite RAS blockade (n = 53) had significantly lower levels of sKlotho [median, 184.7 pg/mL; interquartile range (IQR), 130.5 to 271.8 pg/mL) compared with patients without MA (n = 39; median, 235.2 pg/mL; IQR, 172.0 to 289.4 pg/mL; P = 0.03). Of the cohort, 21% reached the primary outcome. In a competing risk analysis, a 10% higher sKlotho level reduced the incidence of the primary outcome by 12% (hazard ratio, 0.27; 95% confidence interval, 0.15 to 0.52; P < 0.001] independent of traditional risk factors. Patients with sKlotho below the median of 204.4 pg/mL had nearly a fourfold higher cumulative incidence of the primary outcome compared with those above the median (24% vs 6.2%; P = 0.01). CONCLUSIONS In patients with T2DM with relatively preserved eGFR, reduced levels of sKlotho predict renal function decline independent of traditional risk markers. sKlotho is a biomarker of renal dysfunction and a potential treatment target for renoprotection in T2DM.
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Affiliation(s)
- Nikolaos Fountoulakis
- School of Cardiovascular Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom
| | - Giuseppe Maltese
- School of Cardiovascular Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom
| | - Luigi Gnudi
- School of Cardiovascular Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom
| | - Janaka Karalliedde
- School of Cardiovascular Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom
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26
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Oh HJ, Nam BY, Wu M, Kim S, Park J, Kang S, Park JT, Yoo TH, Kang SW, Han SH. Klotho plays a protective role against glomerular hypertrophy in a cell cycle-dependent manner in diabetic nephropathy. Am J Physiol Renal Physiol 2018; 315:F791-F805. [PMID: 29638159 DOI: 10.1152/ajprenal.00462.2017] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
There are few studies on the effect of klotho on podocytes in diabetic nephropathy. Thus, we tested whether klotho exerts a protective effect against glomerular injury in diabetes. Mouse podocytes were cultured in media containing 5.6 or 30 mM glucose(HG) with or without 200 pM of recombinant klotho (rKL). Additionally, 32 mice were injected intraperitoneally with either diluent( n = 16, C) or with streptozotocin ( n = 16, DM). Control and diabetic mice underwent sham operation and unilateral nephrectomy, respectively. Eight mice from each control and DM group were treated daily with 10 μg·kg-1·day-1 of rKL, using an osmotic minipump. Klotho was expressed in podocytes, and its expression was dependent on peroxisome proliferator-activateed receptor-γ (PPARγ). HG treatment increased the expression of cell cycle-related and apoptotic markers, and these were significantly attenuated by rKL; rKL inhibited the extracellular signal-regulated protein kinase-1/2 and p38 signaling pathways in HG-induced podocyte injury. However, siRNA against klotho gene in HG-treated podocytes failed to aggravate cell cycle arrest and apoptosis. When HG-treated podocytes were incubated in the high-klotho-conditioned medium from tubular epithelial cells, cell injury was significantly attenuated. This effect was not observed when klotho was inhibited by siRNA. In vivo, the expressions of cell cycle-related and apoptotic markers were increased in diabetic mice compared with controls, which were significantly decreased by rKL. Glomerular hypertrophy (GH) and increased profibrotic markers were significantly alleviated after rKL administration. These results showed that klotho was expressed in glomerular podocytes that and its expression was regulated by PPARγ. Additionally, administration of rKL attenuated GH via a cell cycle-dependent mechanism and decreased apoptosis.
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Affiliation(s)
- Hyung Jung Oh
- Ewha Institute of Convergence Medicine, Ewha Womans University Mokdong Hospital, Seoul, Republic of Korea
| | - Bo Young Nam
- Department of Internal Medicine, College of Medicine, Severance Biomedical Science Institute, Brain Korea 21 PLUS, Yonsei University, Seoul, Republic of Korea
| | - Meiyan Wu
- Department of Internal Medicine, College of Medicine, Severance Biomedical Science Institute, Brain Korea 21 PLUS, Yonsei University, Seoul, Republic of Korea
| | - Seonghun Kim
- Department of Internal Medicine, College of Medicine, Severance Biomedical Science Institute, Brain Korea 21 PLUS, Yonsei University, Seoul, Republic of Korea
| | - Jimin Park
- Department of Internal Medicine, College of Medicine, Severance Biomedical Science Institute, Brain Korea 21 PLUS, Yonsei University, Seoul, Republic of Korea
| | - Sukyung Kang
- Department of Internal Medicine, College of Medicine, Severance Biomedical Science Institute, Brain Korea 21 PLUS, Yonsei University, Seoul, Republic of Korea
| | - Jung Tak Park
- Divison of Nephrology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.,Institute of Kidney Disease Research, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Tae-Hyun Yoo
- Divison of Nephrology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.,Institute of Kidney Disease Research, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Shin-Wook Kang
- Department of Internal Medicine, College of Medicine, Severance Biomedical Science Institute, Brain Korea 21 PLUS, Yonsei University, Seoul, Republic of Korea.,Divison of Nephrology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.,Institute of Kidney Disease Research, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seung Hyeok Han
- Divison of Nephrology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.,Institute of Kidney Disease Research, Yonsei University College of Medicine, Seoul, Republic of Korea
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27
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Xu Y, Peng H, Ke B. α-klotho and anemia in patients with chronic kidney disease patients: A new perspective. Exp Ther Med 2017; 14:5691-5695. [PMID: 29250136 PMCID: PMC5729369 DOI: 10.3892/etm.2017.5287] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 04/11/2017] [Indexed: 12/17/2022] Open
Abstract
Normocytic normochromic anemia is a common complication of chronic kidney disease (CKD) and is associated with numerous adverse consequences. Certain symptoms previously attributed to CKD are now known to be a consequence of anemia. Anemia contributes to an increased cardiac output, and the development of left ventricular hypertrophy, angina and congestive heart failure, leading to high morbidity and mortality in patients with CKD. The multifunctional α-klotho (KL) protein, which is predominantly expressed in the kidneys, is associated with the occurrence of anemia in patients with CKD. The present review presents current evidence on the potential role of α-KL in renal anemia. Low expression of α-KL appears to improve anemia in patients with CKD, and has been hypothesized to be a compensatory mechanism to attenuate the effects of anemia in patients with CKD. Further understanding of the role of α-KL in renal anemia may offer novel insights into the treatment of patients with CKD complicated with anemia.
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Affiliation(s)
- Yang Xu
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Hao Peng
- Nanchang University School of Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Ben Ke
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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28
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Huang W, Liu H, Zhu S, Woodson M, Liu R, Tilton RG, Miller JD, Zhang W. Sirt6 deficiency results in progression of glomerular injury in the kidney. Aging (Albany NY) 2017; 9:1069-1083. [PMID: 28351995 PMCID: PMC5391219 DOI: 10.18632/aging.101214] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Accepted: 03/18/2017] [Indexed: 02/06/2023]
Abstract
Aging is associated with an increased incidence and prevalence of renal glomerular diseases. Sirtuin (Sirt) 6, a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase, has been shown to protect against multiple age-associated phenotypes; however it is unknown whether Sirt6 has a direct pathophysiologic role in the kidney. In the present study, we demonstrate that Sirt6 is expressed in the kidney and aging Sirt6-deficient mice exhibit renal hypertrophy with glomerular enlargement. Sirt6 deletion induces podocyte injury, including decreases in slit diaphragm proteins, foot process effacement, and cellular loss, resulting in proteinuria. Knockdown of Sirt6 in cultured primary murine podocytes induces shape changes with loss of process formation and cell apoptosis. Moreover, Sirt6 deficiency results in progressive renal inflammation and fibrosis. Collectively, these data provide compelling evidence that Sirt6 is important for podocyte homeostasis and maintenance of glomerular function, and warrant further investigation into the role of Sirt6 in age-associated kidney dysfunction.
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Affiliation(s)
- Wen Huang
- Department of Healthcare, Qianfoshan Hospital Affiliated to Shandong University, Jinan, China.,Department of Ophthalmology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Hua Liu
- Center for Biomedical Engineering, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Shuang Zhu
- Department of Ophthalmology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Michael Woodson
- Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Rong Liu
- Department of Ophthalmology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Ronald G Tilton
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Jordan D Miller
- Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Wenbo Zhang
- Department of Ophthalmology, University of Texas Medical Branch, Galveston, TX 77555, USA.,Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555, USA
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29
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Maltese G, Fountoulakis N, Siow RC, Gnudi L, Karalliedde J. Perturbations of the anti-ageing hormone Klotho in patients with type 1 diabetes and microalbuminuria. Diabetologia 2017; 60:911-914. [PMID: 28194484 PMCID: PMC6518370 DOI: 10.1007/s00125-017-4219-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 12/09/2016] [Indexed: 11/13/2022]
Abstract
AIMS/HYPOTHESIS Patients with type 1 diabetes and microalbuminuria are at high risk of cardiovascular disease (CVD) and end-stage renal disease. Soluble Klotho is an anti-ageing circulating hormone involved in phosphate metabolism and vascular homeostasis through protective effects on the endothelium and antioxidant actions. The role of soluble Klotho in patients with type 1 diabetes and microalbuminuria is unknown. METHODS In a cross-sectional single-centre study we evaluated the levels of circulating serum soluble Klotho in 33 participants with type 1 diabetes and a history of microalbuminuria (receiving renin-angiotensin system [RAS] inhibitors) and 45 participants with type 1 diabetes without a history of microalbuminuria (not receiving RAS or other antihypertensive drugs). All participants had an eGFR >45 ml/min, duration of diabetes >20 years and no history of CVD. Serum soluble Klotho levels were measured by a validated immunoassay. RESULTS Participants with microalbuminuria had significantly lower levels of serum Klotho compared with those without microalbuminuria (median [interquartile range], 659.3 [525.3, 827.6] vs 787.7 [629.5, 1007]; p = 0.023). This difference persisted after adjustment for variables including age and eGFR. In a subgroup of 30 individuals with and without microalbuminuria, other markers of phosphate balance were not significantly different. CONCLUSIONS/INTERPRETATION In individuals with type 1 diabetes, microalbuminuria is associated with soluble Klotho deficiency. Further studies are required to determine whether soluble Klotho is causally related to the development of cardio-renal disease in type 1 diabetes.
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Affiliation(s)
- Giuseppe Maltese
- Unit for Metabolic Medicine, Cardiovascular Division, Faculty of Life Sciences and Medicine, King's College London, 150 Stamford Street, London, SE1 9NH, UK.
| | - Nikolaos Fountoulakis
- Unit for Metabolic Medicine, Cardiovascular Division, Faculty of Life Sciences and Medicine, King's College London, 150 Stamford Street, London, SE1 9NH, UK
| | - Richard C Siow
- Unit for Metabolic Medicine, Cardiovascular Division, Faculty of Life Sciences and Medicine, King's College London, 150 Stamford Street, London, SE1 9NH, UK
| | - Luigi Gnudi
- Unit for Metabolic Medicine, Cardiovascular Division, Faculty of Life Sciences and Medicine, King's College London, 150 Stamford Street, London, SE1 9NH, UK
| | - Janaka Karalliedde
- Unit for Metabolic Medicine, Cardiovascular Division, Faculty of Life Sciences and Medicine, King's College London, 150 Stamford Street, London, SE1 9NH, UK
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30
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Kalaitzidis RG, Duni A, Siamopoulos KC. Klotho, the Holy Grail of the kidney: from salt sensitivity to chronic kidney disease. Int Urol Nephrol 2016; 48:1657-66. [PMID: 27215557 DOI: 10.1007/s11255-016-1325-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 05/17/2016] [Indexed: 01/05/2023]
Abstract
The Klotho gene displays an extremely shortened life span with loss of function missense mutations leading to premature multiple organ failure, thus resembling human premature aging syndromes. The transmembrane form of Klotho protein functions as an obligatory co-receptor for FGF23. Klotho and FGF23 are crucial components for the regulation of vitamin D metabolism and subsequently blood phosphate levels. The secreted Klotho protein has multiple regulatory functions, including effects on electrolyte homeostasis, on growth factor pathways as well as on oxidative stress, which are currently the object of extensive research. Klotho protein deficiency is observed in many experimental and clinical disease models. Genetic polymorphisms such as the G-395A polymorphism in the promoter region of the Klotho gene have been associated with the development of essential hypertension. The kidneys are the primary site of Klotho production, and renal Klotho is decreased in CKD, followed by a reduction in plasma Klotho. Klotho deficiency has been both associated with progression of CKD as well as with its cardinal systemic manifestations, including cardiovascular disease. Thus, Klotho has been suggested both as a risk biomarker for early detection of CKD and additionally as a potential therapeutic tool in the future.
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Affiliation(s)
- Rigas G Kalaitzidis
- Department of Nephrology, University Hospital of Ioannina, Ioannina, Greece.
| | - Anila Duni
- Department of Nephrology, University Hospital of Ioannina, Ioannina, Greece
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