Wnt/β-catenin/RAS signaling mediates age-related renal fibrosis and is associated with mitochondrial dysfunction.

Aging Cell. 2019 Oct; 18(5): e13004. Published online 2019 Jul 18. doi: 10.1111/acel.13004 PMCID: PMC6718575 PMID: 31318148 Wnt/β‐catenin/RAS signaling mediates age‐related renal fibrosis and is associated with mitochondrial dysfunction Jinhua Miao, 1 Jiafeng Liu, 1 Jing Niu, 1 Yunfang Zhang, 2 Weiwei Shen, 1 Congwei Luo, 1 Yahong Liu, 1 Chuanjiang Li, 3 Hongyan Li, 2 Peiliang Yang, 1 Youhua Liu, 1 Fan Fan Hou, 1 and Lili Zhou 1 Jinhua Miao 1 Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China, Find articles by Jinhua Miao Jiafeng Liu 1 Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China, Find articles by Jiafeng Liu Jing Niu 1 Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China, Find articles by Jing Niu Yunfang Zhang 2 Department of Nephrology, Huadu District People’s Hospital, Southern Medical University, Guangzhou, China, Find articles by Yunfang Zhang Weiwei Shen 1 Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China, Find articles by Weiwei Shen Congwei Luo 1 Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China, Find articles by Congwei Luo Yahong Liu 1 Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China, Find articles by Yahong Liu Chuanjiang Li 3 Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China, Find articles by Chuanjiang Li Hongyan Li 2 Department of Nephrology, Huadu District People’s Hospital, Southern Medical University, Guangzhou, China, Find articles by Hongyan Li Peiliang Yang 1 Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China, Find articles by Peiliang Yang Youhua Liu 1 Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China, Find articles by Youhua Liu Fan Fan Hou 1 Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China, Find articles by Fan Fan Hou Lili Zhou 1 Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China, Find articles by Lili Zhou Author information Article notes Copyright and License information Disclaimer 1 Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China, 2 Department of Nephrology, Huadu District People’s Hospital, Southern Medical University, Guangzhou, China, 3 Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China, Lili Zhou, Email: nc.ude.ums@037ilnij. Corresponding author. *Correspondence Lili Zhou, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Email: nc.ude.ums@037ilnij, Received 2018 Oct 11; Revised 2019 Jun 12; Accepted 2019 Jun 24. Copyright © 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Associated DataSupplementary Materials   ACEL-18-e13004-s001.jpg (1.3M) GUID: 0DBBF561-DE8E-4E93-A0AA-32F5614C50FA   ACEL-18-e13004-s002.jpg (322K) GUID: B84FDFB6-1D62-4A57-9AE5-967DC04AED95   ACEL-18-e13004-s003.jpg (269K) GUID: DB105C89-51D9-47B4-B0A2-7C06E6D0F18D   ACEL-18-e13004-s004.jpg (482K) GUID: 4EEE139F-7C9E-4F0A-9486-F3A9BCDA2F16   ACEL-18-e13004-s005.jpg (2.3M) GUID: 92E801B6-11DF-493A-A7C1-2CCA0C1A6A7D   ACEL-18-e13004-s006.jpg (1.2M) GUID: DE991C0B-FE45-4F06-BFEE-56AF32A29184   ACEL-18-e13004-s007.jpg (1.4M) GUID: 5947D574-9A72-4073-866B-F0943E846EB7   ACEL-18-e13004-s008.jpg (1.0M) GUID: 23D9B1FB-2A4D-4924-81A9-3D1DDAFDE62E   ACEL-18-e13004-s009.docx (12K) GUID: 1DD2A24A-2AFD-4DCA-866B-A548F3278145 Abstract Renal fibrosis is the common pathological feature in a variety of chronic kidney diseases. Aging is highly associated with the progression of renal fibrosis. Among several determinants, mitochondrial dysfunction plays an important role in aging. However, the underlying mechanisms of mitochondrial dysfunction in age‐related renal fibrosis are not elucidated. Herein, we found that Wnt/β‐catenin signaling and renin–angiotensin system (RAS) activity were upregulated in aging kidneys. Concomitantly, mitochondrial mass and functions were impaired with aging. Ectopic expression of Klotho, an antagonist of endogenous Wnt/β‐catenin activity, abolished renal fibrosis in d‐galactose (d‐gal)‐induced accelerated aging mouse model and significantly protected renal mitochondrial functions by preserving mass and diminishing the production of reactive oxygen species. In an established aging mouse model, dickkopf 1, a more specific Wnt inhibitor, and the mitochondria‐targeted antioxidant mitoquinone restored mitochondrial mass and attenuated tubular senescence and renal fibrosis. In a human proximal tubular cell line (HKC‐8), ectopic expression of Wnt1 decreased biogenesis and induced dysfunction of mitochondria, and triggered cellular senescence. Moreover, d‐gal triggered the transduction of Wnt/β‐catenin signaling, which further activated angiotensin type 1 receptor (AT1), and then decreased the mitochondrial mass and increased cellular senescence in HKC‐8 cells and primary cultured renal tubular cells. These effects were inhibited by AT1 blocker of losartan. These results suggest inhibition of Wnt/β‐catenin signaling and the RAS could slow the onset of age‐related mitochondrial dysfunction and renal fibrosis. Taken together, our results indicate that Wnt/β‐catenin/RAS signaling mediate (...truncated)