Restoration of SIRT3 Expression in Aged Mice Alleviates UUO-Induced Renal Fibrosis by Reducing GSK-3β Hyperacetylation.

Jing Wang, Xiang Ren, Huan Lu, Zihao Guo, Xing Li, Yiqun Tian, Yisheng Yin, Zhenliang Qin, Kun Yun, Minglong Wu, Gang Chen, Xiaoyong Zeng

Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, 430030, China.Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, 430030, China. · pubmed

Paper

Abstract

Aging increases the vulnerability of kidneys to injury and impairs their regenerative capacity. SIRT3 expression declines with aging and is associated with multiple age-related pathologies. The expression profile and functional role of SIRT3 in renal aging remain unclear. Here, SIRT3 expression in aging kidneys is assessed and analyzed for its promoter methylation patterns using methylation-specific PCR (MSP). It is found that aging exacerbates UUO-induced renal fibrosis, associated with downregulated SIRT3 expression. Mechanistically, age-related SIRT3 downregulation is mediated by hypermethylation of its promoter region. SIRT3 knockout exacerbated renal fibrosis in young mice subjected to UUO, whereas SIRT3 overexpression attenuated fibrosis in aged UUO mice. Integration of RNA-seq and immunoprecipitation-mass spectrometry (IP-MS) analyses revealed that SIRT3 deficiency leads to hyperacetylation of GSK3β at lysine 15 (K15). This K15 hyperacetylation inhibited GSK3β activity, consequently stabilizing its substrate β-catenin. Furthermore, self-assembled PEG-PCL-PEG micelles are designed and synthesized to encapsulate hydrophobic honokiol (HKL). These micelles significantly enhanced the aqueous solubility and oral bioavailability of free HKL, maintained stable blood concentrations, and ultimately improved its anti-fibrotic efficacy. These findings propose novel therapeutic strategies for managing renal fibrosis in the aging population and provide a foundation for developing new drugs and combination therapies.

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Research summary

Restoration of SIRT3 expression in aged mice alleviates UUO-induced renal fibrosis by reducing GSK-3β hyperacetylation. The paper addresses the decline of SIRT3 with aging and its role in renal fibrosis, proposing a potential therapeutic strategy that targets a root cause of age-related decline in kidney function.

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