HSP90-specific inhibitor, PSY-2-12, ameliorates cellular senescence via activating autophagy: A potential senotherapeutic target against acute kidney injury.

Abstract

An unexpected senotherapeutic function of heat shock protein 90 (HSP90) inhibitors-drugs long developed as cancer therapeutics-has recently been revealed. In this study, we employed an HSP90-specific inhibitor, PSY-2-12 (PSY), to explore its potential therapeutic application as a senomorphic agent. We demonstrated that PSY, at non-toxic concentrations, reduces cellular senescence in both cisplatin (CP)-induced senescent kidney proximal tubular cells and angiotensin II-induced senescent human umbilical vein endothelial cells. The anti-senescent effect of PSY was further confirmed in a mouse model of CP-induced acute kidney injury (AKI). PSY treatment attenuated CP-induced kidney injury, as evidenced by decreased levels of urea, creatinine, and kidney injury molecule-1, and ameliorated CP-induced senescence, as shown by reduced β-galactosidase staining and p16 expression, along with increased lamin B1 levels compared with controls. Mechanistically, we found that PSY exerts its senotherapeutic effects through beclin-1-mediated stimulation of autophagy. PSY enhanced beclin-1 expression and autophagic flux in CP-treated proximal tubular cells, while inhibition of autophagy reversed the senotherapeutic effects of PSY. Similarly, beclin-1 knockdown abolished the protective effects. In summary, our results suggest that PSY, an HSP90-specific inhibitor, may serve as a promising senomorphic therapeutic agent for the treatment of AKI.