Sirtuin 3 Promotes Renal Gluconeogenesis in Fibrotic Kidneys

Background: Decreased renal gluconeogenesis is currently identified as a hallmark of chronic kidney disease, which may contribute to renal fibrosis. Sirt3 is a crucial metabolic sensor that regulates ATP generation, mitochondrial adaptive response to stress, and glucose metabolism. Sirt3 is renal protective in fibrotic kidneys, however its underlying mechanisms is not completely known. Methods: Sirt3 inhibitor (3-TYP) was used to evaluate the effect of Sirt3 on renal fibrosis and renal gluconeogenesis in UUO mice. The effect of Sirt3 on proximal tubular cells was evaluated in in vitro, ex vivo and in vivo models of renal fibrosis. Mechanistically, the effect of Sirt3 on metabolic transcription factors FOXO1 was evaluated. Finally, pharmaceutical activation of Sirt3 by its agonist HKL on renal gluconeogenesis and systemic glucose metabolism was assessed in in vivo model. Results: Decreased sirt3 expression was accompanied by reduced expression of gluconeogenesis rate-limiting enzymes (PCK1, FBP1) in UUO kidneys. Sirt3 is co-localized with PCK1 and FBP1 expression in proximal tubular cells of fibrotic kidneys. Sirt3 adenovirus alleviated renal fibrosis and improved the glucose homeostasis in vitro, ex vivo and in vivo models of renal fibrosis. Furthermore, Sirt3 agonist or overexpressed of sirt3 by adenovirus improved gluconeogenesis through activation of metabolic transcription factor FOXO1 and PGC-1α in in vitro and ex vivo models. A direct interaction between FOXO1 and Sirt3 was revealed through co-immunoprecipitation experiment by using primary kidney tubular cells. FOXO1 inhibitor abolished the pro-gluconeogenic effect of Sirt3 agonist in fibrotic renal cells. Pharmaceutical activation of Sirt3 improved renal gluconeogenesis and systemic glucose metabolism in UUO mice. Conclusion: Sirt 3 promotes renal gluconeogenesis in proximal tubular cells of fibrotic kidneys through direct interaction and up-regulation of FOXO1. Pharmaceutical activation of Sirt3 could be a new strategy to improve glucose metabolism in chronic kidney disease patients. Funding: Government Support – Non-U.S.Diagram depicts SIRT3 regulating gluconeogenesis in renal fibrosis