FFAR4 improves the senescence of tubular epithelial cells by AMPK/SirT3 signaling in acute kidney injury

作者：Letian Yang, Bo Wang, Fan Guo, Rongshuang Huang, Yan Liang, Lingzhi Li, Sibei Tao, Ting Yin, Ping Fu, Liang Ma · 发表于：Signal Transduction and Targeted Therapy · 年份：2022 · DOI：10.1038/s41392-022-01254-x · 被引用次数：119 · 研究领域：Acute Kidney Injury Research、Biomedical Research and Pathophysiology、Chemotherapy-induced organ toxicity mitigation

Acute kidney injury (AKI) is a serious clinical complication with high morbidity and mortality rates. Despite substantial progress in understanding the mechanism of AKI, no effective therapy is available for treatment or prevention. We previously found that G protein-coupled receptor (GPCR) family member free fatty acid receptor 4 (FFAR4) agonist TUG891 alleviated kidney dysfunction and tubular injury in AKI mice. However, the versatile role of FFAR4 in kidney has not been well characterized. In the study, the expression of FFAR4 was abnormally decreased in tubular epithelial cells (TECs) of cisplatin, cecal ligation/perforation and ischemia/reperfusion injury-induced AKI mice, respectively. Systemic and conditional TEC-specific knockout of FFAR4 aggravated renal function and pathological damage, whereas FFAR4 activation by TUG-891 alleviated the severity of disease in cisplatin-induced AKI mice. Notably, FFAR4, as a key determinant, was firstly explored to regulate cellular senescence both in injured kidneys of AKI mice and TECs, which was indicated by senescence-associated β-galactosidase (SA-β-gal) activity, marker protein p53, p21, Lamin B1, phospho-histone H2A.X, phospho-Rb expression, and secretory phenotype IL-6 level. Mechanistically, pharmacological activation and overexpression of FFAR4 reversed the decrease of aging-related SirT3 protein, where FFAR4 regulated SirT3 expression to exhibit anti-senescent effect via Gq subunit-mediated CaMKKβ/AMPK signaling in cisplat...