CaMKII phosphorylation promotes renal fibrosis in cisplatin induced chronic kidney disease via Smad 2/3 activation.

Cisplatin-induced nephrotoxicity limits its clinical use as an anticancer drug. Acute kidney injury (AKI) caused by cisplatin can progress to chronic kidney disease (CKD), which is characterized by fibrosis. Effective treatments for cisplatin-induced CKD are unavailable due to a lack of proper understanding of the underlying mechanisms. Calcium/calmodulin-dependent protein kinase II (CaMKII) has been implicated in fibrotic progression in various renal disorders; however, its role in cisplatin-induced renal fibrosis remains unclear. In this study, we demonstrate that CaMKII activation is a critical mediator of cisplatin-induced renal fibrosis both in vivo and in vitro. Repeated cisplatin exposure in C57BL/6 mice resulted in increased CaMKII phosphorylation, renal dysfunction, histological injury, upregulation of profibrotic markers, including α-SMA, collagen I, and vimentin, and downregulation of epithelial marker E-Cadherin. Similarly, NRK52E and HK2 renal epithelial cells exposed to low-dose, repeated cisplatin exhibited enhanced CaMKII activation and elevated expression of α-SMA, collagen I, vimentin, and decreased E-cadherin expression. Pharmacological inhibition of CaMKII with KN93 significantly improved renal function and attenuated fibrotic and histopathological changes in vivo while also reversing fibrotic phenotypes in vitro. Mechanistically, cisplatin-induced CaMKII phosphorylation activated the Smad2/3 signalling cascade, whereas KN93 treatment suppressed this pathway, reducing fibrogenic responses. Collectively, these findings identify CaMKII as a key regulator of renal fibrosis in cisplatin-induced CKD and suggest that targeting CaMKII may represent a promising therapeutic strategy to mitigate long-term nephrotoxicity in patients receiving cisplatin chemotherapy.