Enhanced TRPC3 transcription through AT1R/PKA/CREB signaling contributes to mitochondrial dysfunction in renal tubular epithelial cells in D‐galactose‐induced accelerated aging mice

Abstract

AbstractAging‐associated renal dysfunction promotes the pathogenesis of chronic kidney disease. Mitochondrial dysfunction in renal tubular epithelial cells is a hallmark of senescence and leads to accelerated progression of renal disorders. Dysregulated calcium profiles in mitochondria contribute to aging‐associated disorders, but the detailed mechanism of this process is not clear. In this study, modulation of the sirtuin 1/angiotensin II type 1 receptor (Sirt1/AT1R) pathway partially attenuated renal glomerular sclerosis, tubular atrophy, and interstitial fibrosis in D‐galactose (D‐gal)‐induced accelerated aging mice. Moreover, modulation of the Sirt1/AT1R pathway improved mitochondrial dysfunction induced by D‐gal treatment. Transient receptor potential channel, subtype C, member 3 (TRPC3) upregulation mediated dysregulated cellular and mitochondrial calcium homeostasis during aging. Furthermore, knockdown or knockout (KO) of Trpc3 in mice ameliorated D‐gal‐induced mitochondrial reactive oxygen species production, membrane potential deterioration, and energy metabolism disorder. Mechanistically, activation of the AT1R/PKA pathway promoted CREB phosphorylation and nucleation of CRE2 binding to the Trpc3 promoter (−1659 to −1648 bp) to enhance transcription. Trpc3 KO significantly improved the renal disorder and cell senescence in D‐gal‐induced mice. Taken together, these results indicate that TRPC3 upregulation mediates age‐related renal disorder and is associated with mitochondrial calcium overload and dysfunction. TRPC3 is a promising therapeutic target for aging‐associated renal disorders.