Akira Maeda, Yoshihiro Iwashita, Junichi Iiyama, Ryosuke Date, Jingxuan Zhang, Daisuke Fujimoto, Yutaka Kakizoe, Yuichiro Izumi, Masataka Adachi, Hideki Yokoi, Masashi Mukoyama, Takashige Kuwabara
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. While simultaneous thermal stimulation with cisplatin showed no protective effect, thermal preconditioning (TP) performed 6 hours prior exerted significant cytoprotection. This effect was mediated by early TRPV4 activation, which triggered enhanced Ca²⁺ influx and subsequent upregulation of 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.