The protective role of TRPV4-mediated HSP27 preemptive induction by thermal preconditioning against cisplatin-induced...

Cisplatin is a widely used chemotherapeutic agent whose nephrotoxicity limits its clinical utility. Here, we investigated whether thermal therapy alleviates cisplatin-induced injury in renal proximal tubular epithelial cells (NRK52E) and explored the underlying molecular mechanisms. Although simultaneous thermal stimulation with cisplatin showed no protective effect, thermal preconditioning (TP) performed 6 h prior exerted significant cytoprotection. This effect was mediated by early TRP vanilloid 4 (TRPV4) activation, which triggered enhanced Ca²⁺ influx and subsequent upregulation of heat shock protein 27 (HSP27), a cytoprotective chaperone. Inhibition or knockdown of TRPV4 or HSP27 abolished the protective effects, confirming their essential roles. These findings suggest that TP induces a preemptive protective response in renal tubular cells, highlighting TRPV4-mediated HSP27 expression as a key mechanism for reducing cisplatin nephrotoxicity.NEW & NOTEWORTHY Thermal preconditioning (TP) performed 6 h before cisplatin exposure protected against cisplatin-induced tubular injury, unlike simultaneous heating. TP activated TRPV4 channels, inducing Ca²⁺ influx and upregulating the cytoprotective chaperone HSP27. Inhibition or knockdown of TRPV4 or HSP27 abolished this protection, confirming their critical roles. These results indicate that TRPV4-mediated HSP27 induction is a key mechanism by which TP elicits preemptive defense against cisplatin-induced nephrotoxicity.