Nephroprotective effect of exogenous hydrogen sulfide donor against cyclophosphamide-induced toxicity is mediated by Nrf2/HO-1/NF-κB signaling pathway

Abstract

AimCyclophosphamide (CP) is an effective anticancer and immunosuppressive agent. However, it induces nephrotoxicity that limits its use. This study explored the effect of H2S, an important biological signaling molecule with a cytoprotective activity, on CP-induced nephrotoxicity. MethodsMale Wistar rats were treated with saline or NaHS (100 μM/kg/day, H2S donor) or dl-propargylglycine (PAG) (30 mg/kg/day, H2S blocker) for 10 days before a single i.p injection of CP (200 mg/kg). Then, rats were sacrificed, and renal functions were assessed in serum. Histopathological changes, as well as oxidant defenses, inflammatory and apoptotic markers in the renal tissue, were evaluated. Key findingsPretreatment with NaHS significantly reduced the urea and creatinine levels that were elevated in CP-intoxicated rats. NaHS increased the expression of the cytoprotective nuclear factor erythroid 2-related factor 2 (Nrf2) and its subsequent antioxidant proteins; heme oxygenase-1 (HO-1), NAD(P) H quinone oxidoreductase 1 (NQO1), reduced glutathione (GSH) and superoxide dismutase (SOD). Moreover, NaHS prohibited the histopathological damage induced by CP. The inhibition of caspase-3 and nuclear factor kappa B (NF-κB) supported the protective role of H2S against CP-induced kidney damage. On the other hand, blocking endogenous H2S did not provide a more significant deterioration in CP-induced nephrotoxicity in terms of oxidative stress or inflammatory status. SignificanceExogenous H2S donors exhibited a protective effect against CP-induced nephrotoxicity, which may be mediated via the Nrf2/HO-1/NF-κB signaling pathway. However, endogenous H2S may be insufficient to protect the cell against the induced oxidative damage. This approach provides a novel target to prevent nephrotoxicity of CP.