Cilostazol or canagliflozin mitigates Cyclosporine A-induced nephrotoxicity by modulating the STAMP2-mTOR-AMPK signaling pathway and autophagy in a rat model

Cyclosporine A is a highly used immunosuppressive medication despite its nephrotoxicity side effect restricting its use. We investigated the potential renoprotective role of cilostazol (CLZ) and canagliflozin (CGF) against Cyclosporine A-induced nephrotoxicity in rats. Rats were administered oral Cyclosporine A (25 mg/kg/day) for nephrotoxicity and treated with either CLZ or CGF for 21 days at doses (10 mg/kg/day and 20 mg/kg/day) for both one hour before Cyclosporine A administration Rats were evaluated for body weight, serum renal injury biomarkers, histopathology, immunohistochemistry, histomorphometry, and mRNA and protein expression levels of six transmembrane proteins of prostate 2 (STAMP2) and inflammation markers, in addition to mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) renal tissue levels. Cyclosporine A-induced kidney injury in the form of marked attenuation of nephrotoxicity and inflammatory markers and elevation of mRNA and protein expression levels of STAMP2, leading to high concentration levels of AMPK with low mTOR inducing autophagy. We noticed that both CLZ and CGF high doses prompted the highest renoprotective activities contrary to the low dose. These previous beneficial effects of CLZ and CGF could be due to modulation of the STAMP2-mTOR-AMPK signaling pathway, resulting in improvement of glomerular and tubular degeneration, LC3-II immunohistochemical expression, and histomorphometric parameters. Our study adds some experimental proof that CLZ and CGF could be effective alternatives for mitigating the nephrotoxicity in patients receiving Cyclosporine A therapy for autoimmune disorders or after solid organ transplants. • Cilostazol and canagliflozin alleviated the nephrotoxicity via STAMP2-mTOR-AMPK pathway. • Both therapies illustrated anti-inflammatory activities and modulators of autophagy. • Both therapies improved the glomerular and tubular degeneration, LC3-II immunohistochemical expression, and histomorphometric parameters. • The higher doses of both therapies prompted the highest renoprotective activities versus the lower doses. • The renoprotective beneficial effects of both therapies in CsA-induced nephrotoxicity model were proven.