Thesis & Dissertations

Modulation of EDHF-Mediated Renovascular Relaxation by CYP Inducers/Inhibitors in Cyclosporine Nephrotoxicity in Rats


Nephrotoxicity is a serious side effect for the immunosuppressant drug cyclosporine (CSA). This study tested the hypothesis that the concurrent administration of calcium channel blockers (CCBs) such as verapamil or nifedipine guard against hypertension and renal dysfunction induced by CSA in rats. Pharmacological, histopathological, biochemical, and molecular studies were performed to investigate possible mechanisms of the detrimental effects of CSA and how they can be mitigated by the concurrent administration of CCBs. The CSA induced hypertension was abolished after the co-treatment with verapamil or nifedipine while they had no effect on associated tachycardia. Rats treated with CSA exhibited clear signs of nephrotoxicity including: proteinuria and elevations in serum creatinine and blood urea nitrogen, deposition of collagen IV in glomerular and tubular areas, and increases in the glomerular and tubular sclerotic index. The concurrent use of either CCB ameliorated these derangements. The inflammatory (NF-κB expression), oxidative (NADPH-oxidase activity, DUOX1/2 expression, reactive oxygen species (ROS) production), and fibrotic (TGF-β1 expression) manifestations of renal toxicity induced by CSA were eliminated upon concurrent administration of CCBs. In addition, CSA reduced the carbachol-induced vasodilations in the isolated perfused phenylephrine-preconstricted kidneys and this effect was coupled by increases in renal ROS generation. Paradoxically, CSA increased carbachol vasodilations and had no effect on ROS generation in preparations infused continuously with L-NAME plus DIC, inferring the capacity of CSA to enhance EDHF-mediated vasodilations under conditions of inhibited NOS/COX activity, suggesting that CSA enhanced renal vasodilations induced by EETs. The potentiating effect of CSA on the EDHF-dependent renal vasodilation induced by carbachol was accentuated in rats treated concurrently with verapamil and abolished by nifedipine. The renal protein expression of CYP2C and CYP4A as well as their vasoactive products were increased in CSA-treated rats. Whereas, CYP2C/EETs effects were abolished by verapamil and intensified by nifedipine, the CYP4A/20-HETE effects were reduced by both CCBs. The increase in carbachol vasodilations in CSA and CSA/verapamil groups were paralleled with similar rises in the inhibitory effect of MSPPOH on carbachol vasodilations, highlighting the involvement of EDHF in these responses. By contrast, HET0016 increased carbachol vasodilations in CSA-treated rats, denoting that the upregulated CYP4A/20-HETE signal might have acted to offset the vasodilatory response. Likewise, in CSA/nifedipine-treated rats the increases in EDHF-mediated vasodilation can be attributed to the decline in CYP4A/20-HETE signal. These results highlight the usefulness of CCBs in negating the CSA-induced nephrotoxicity and predisposing renovascular, biochemical and molecular machineries.


Safaa H Hammoud


Prof. Amal Galal Omar, Prof. Mahmoud El-Mas, Dr. Assaad Eid

List of journals' publication related to the thesis

- CYP4A/CYP2C modulation of the interaction of calcium channel blockers with cyclosporine on EDHF-mediated renal vasodilations in rats - Molecular Mechanisms of the Protective Effects of Calcium Channel Blockers against Cyclosporine Nephrotoxicity in Rats - Molecular Mechanisms of the Protective Effects of Calcium Channel Blockers against Cyclosporine Nephrotoxicity

List of conferences' participation related to the thesis

Experimental Biology 2017