Palliative Role of Zamzam Water against Cyclosporine-Induced Nephrotoxicity through Modulating Autophagy and Apoptosis Crosstalk

Abstract

Cyclosporine (CsA) is considered one of the main components of treatment protocols for organ transplantation owing to its immunosuppressive effect. However, its use is very restricted due to its nephrotoxic effect. ZW is an alkaline fluid rich in various trace elements and has a great ability to stimulate antioxidant processes. This study aimed to investigate the possible mitigating effect of ZW on CsA-induced nephrotoxicity and its underlying mechanisms. Forty rats were allocated into four groups (n = 10): a control group, ZW group, cyclosporine A group (injected subcutaneously (SC) with CsA (20 mg/kg/day)), and cyclosporine A+ Zamzam water group (administered CsA (SC) and ZW as their only drinking water (100 mL/cage/day) for 21 days). Exposure to CsA significantly (p < 0.001) increased the serum creatinine level, lipid peroxidation marker level (malondialdehyde; MDA), and the expression of apoptotic markers procaspase-8, caspase-8, caspase- 9, calpain, cytochrome c, caspas-3, P62, and mTOR in renal tissues. Meanwhile, it markedly decreased (p< 0.001) the autophagic markers (AMPK, ULK-I, ATag5, LC3, and Beclin-1), antiapoptotic Bcl-2, and antioxidant enzymes. Moreover, the administration of CsA caused histological alterations in renal tissues. ZW significantly (p < 0.001) reversed all the changes caused by CsA and conclusively achieved a positive outcome in restraining CsA-induced nephrotoxicity, as indicated by the restoration of the histological architecture, improvement of renal function, inhibition of apoptosis, and enhancement of autophagy via the AMPK/mTOR pathway.