Carvedilol attenuates doxorubicin-evoked renal toxicity in rats: The role of PI3K/AKT/mTOR, Nrf2/HO-1 and Bax/Bcl2 signals

Doxorubicin (DOX) is considered a highly effective antineoplastic agent for different types of cancers. Regretfully, its clinical application is restricted by its renal intoxication. Carvedilol (CAR), a non-selective β-adrenoceptor blocker, possesses unique antioxidant, anti-inflammatory and antifibrotic features. The current investigation was established to investigate the protective impacts and the implicated molecular mechanisms of CAR against DOX-induced renal toxicity in rats. Rats were randomly assigned into three groups: control, DOX and CAR+DOX. DOX was given as a single intraperitoneal dose (30 mg/kg) while CAR was administered as a singular daily dose of 30 mg/kg/P.O. for 14 days. Renal function indicators including BUN, creatinine, KIM-1 and cystatin-C were estimated. Oxidative stress biomarkers including MDA, GSH, and SOD as well as inflammatory mediators as COX-II, TNF-α and IL-6 were also assessed. Western blotting was performed to determine the protein expressions of Nrf2, HO-1, PI3K, Akt and mTOR. The expressions of Bax and Bcl2 were immunohistochemically evaluated in addition to the histological investigation of renal tissue. Our results revealed that CAR restored renal function and counteracted oxidative stress in renal tissue. The inflammatory mediators were significantly reduced. CAR pretreatment caused significant up-regulation of Nrf-2 and HO-1expressions along with marked down-regulation of PI3K, Akt and mTOR expressions. CAR significantly enhanced Bcl2 while significantly diminished Bax renal expressions. Such findings were supported by renal histological features improvement. In conclusion, CAR counteracted the renal damage induced by DOX via suppressing oxidative stress, inflammatory response, and apoptosis through downregulation of PI3K/Akt/mTOR and Bax/Bcl2 and upregulation of Nrf2/HO-1 signals.