Pharmacological activation of SIRT1 alleviates sepsis-associated acute kidney injury by improving renal mitochondrial energy metabolism.

Sepsis-associated acute kidney injury (SA-AKI) is a frequent and severe complication of sepsis and is closely associated with increased mortality. Mitochondrial dysfunction and impaired energy metabolism are important contributors to SA-AKI pathogenesis. Silent information regulator 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, regulates cellular metabolism, oxidative stress, and mitochondrial homeostasis. However, its role in septic renal mitochondrial dysfunction remains incompletely understood. In this study, an LPS-induced NRK-52E rat kidney epithelial cell injury model and a cecal ligation and puncture (CLP)-induced sepsis rat model were established. SIRT1-related signaling was pharmacologically modulated using the SIRT1 activator SRT1720 or the SIRT1 inhibitor EX-527. Cell viability, SIRT1 mRNA and protein abundance, mitochondrial ultrastructure, oxidative stress, mitochondrial membrane potential, ATP content, ATPase activity, and non-esterified fatty acid levels were assessed. LPS exposure reduced SIRT1 expression in NRK-52E cells and was accompanied by decreased cell viability, mitochondrial structural damage, oxidative stress, and impaired energy metabolism. SRT1720 attenuated these changes, whereas EX-527 aggravated them. Similarly, in CLP-induced septic rats, renal SIRT1 expression was decreased, together with renal injury and mitochondrial metabolic dysfunction. SRT1720 ameliorated renal pathological injury and mitochondrial-related abnormalities, whereas EX-527 worsened these changes. These findings suggest that SIRT1 activation attenuates SA-AKI, at least partly by maintaining renal mitochondrial energy homeostasis.