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

AIM

Cyclophosphamide (CP) is an effective anticancer and immunosuppressive agent. However, it induces nephrotoxicity that limits its use. This study explored the effect of HS, an important biological signaling molecule with a cytoprotective activity, on CP-induced nephrotoxicity.

METHODS

Male Wistar rats were treated with saline or NaHS (100 μM/kg/day, HS donor) or dl-propargylglycine (PAG) (30 mg/kg/day, HS 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 FINDINGS

Pretreatment 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 HS against CP-induced kidney damage. On the other hand, blocking endogenous HS did not provide a more significant deterioration in CP-induced nephrotoxicity in terms of oxidative stress or inflammatory status.

SIGNIFICANCE

Exogenous HS donors exhibited a protective effect against CP-induced nephrotoxicity, which may be mediated via the Nrf2/HO-1/NF-κB signaling pathway. However, endogenous HS may be insufficient to protect the cell against the induced oxidative damage. This approach provides a novel target to prevent nephrotoxicity of CP.