Tolvaptan Treatment Ameliorates Cisplatin-Induced Nephropathy

Background: Cisplatin is a widely used platinum-based chemotherapeutic agent that induces cancer cell death through DNA crosslinking. However, its clinical utility is limited by significant nephrotoxicity. We previously demonstrated that modulation of renal tissue osmolarity with Tolvaptan, a selective vasopressin V2 receptor (Avpr2) antagonist, protects against ischemia-reperfusion injury in mice. Here, we investigate whether this protective effect extends to a cisplatin-induced nephropathy model. Methods: C57Bl/6N mice were administered cisplatin (9 mg/kg, once weekly for three weeks) and divided into two groups: one received Tolvaptan via the diet, the other remained untreated. Kidneys and serum were collected three days after the final dose. Renal injury was assessed by Periodic Acid–Schiff and Masson’s Trichrome staining. KIM-1 expression and immune cell infiltration (F4/80 macrophages) were evaluated by immunofluorescence. Results: Tolvaptan reduced the medullary osmotic gradient from the outer stripe of the outer medulla (OSOM) to the papilla. In this region, where osmolarity is significantly altered by Tolvaptan, we observed a notable reduction in cisplatin-induced KIM-1 expression and decreased F4/80 macrophage infiltration, indicating attenuated injury and inflammation. Conclusion: Our findings suggest that modulation of Avpr2-dependent medullary osmolality represents a promising therapeutic strategy for renoprotection across diverse models of kidney injury. Funding: Government Support – Non-U.S.