Down-Regulation of TFEB With Defective Autophagy in the Susceptibility of Aging Kidneys to Septic Acute Kidney Injury.

Sepsis-associated acute kidney injury (SA-AKI) is a common and devastating disease that has a significantly higher incidence and greater severity in elderly patients, but the molecular basis underlying SA-AKI in the elderly is largely unknown. Recent studies have proved autophagy as an intrinsic protective mechanism against AKI; however, the role and regulation of autophagy in aging kidneys remain unclear. Here we demonstrate that defective autophagy activation in aging kidneys is a key to their susceptibility to SA-AKI. In our experiments, the ability of autophagy activation was impaired in aging kidneys in response to SA-AKI in mice. In vitro, activation of autophagy with TAT-Beclin-1 peptide mitigated lipopolysaccharide (LPS)-induced apoptosis and inflammation in senescent renal proximal tubular cells. Single-cell sequencing revealed significant age-related alterations in autophagy-associated genes in septic AKI, including TFEB. Overexpression of TFEB could partially restore autophagic activity in senescent renal tubular cells and protect them from LPS-induced damage. Moreover, in vivo treatment with the curcumin analog C1 (a TFEB activator) enhanced autophagic function in aging kidneys and reduced LPS-induced AKI. These results demonstrate the defective autophagy activation in aging kidneys, which contributes to the SA-AKI sensitivity and susceptibility in the elderly, suggesting a therapeutic strategy by enhancing autophagy.