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

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 mediates age-related renal fibrosis and is associated with mitochondrial dysfunction.

• Authors: Jinhua Miao, Jiafeng Liu, Jing Niu, Yunfang Zhang, Weiwei Shen, Congwei Luo, Yahong Liu, Chuanjiang Li, Hongyan Li, Peiliang Yang, Youhua Liu, Fan Fan Hou, Lili Zhou
• Journal: Aging cell (Aging Cell) Vol. 18 Issue 5 Pg. e13004 (10 2019) ISSN: 1474-9726 [Electronic] England
• PMID: 31318148 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Chemical References

• Reactive Oxygen Species
• beta Catenin
• Galactose

Topics

• Aging (drug effects, metabolism)
• Animals
• Fibrosis (drug therapy, metabolism)
• Galactose (administration & dosage, pharmacology)
• Injections, Subcutaneous
• Kidney Diseases (drug therapy, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mitochondria (drug effects, metabolism)
• Reactive Oxygen Species (antagonists & inhibitors, metabolism)
• Renin-Angiotensin System (drug effects)
• Wnt Signaling Pathway (drug effects)
• beta Catenin (antagonists & inhibitors, metabolism)