Angiotensin II receptor blockade alleviates calcineurin inhibitor nephrotoxicity by restoring cyclooxygenase 2 expression in kidney cortex

Aim The use of calcineurin inhibitors such as cyclosporine A (CsA) for immunosuppression after solid organ transplantation is commonly limited by renal side effects. CsA-induced deterioration glomerular filtration rate and sodium retention may be related to juxtaglomerular dysregulation a result suppressed cyclooxygenase 2 (COX-2) stimulated renin biosynthesis. We tested whether COX-2 suppression caused hyperactive renin-angiotensin system (RAS) RAS inhibition alleviate the Methods Rats received CsA, inhibitor candesartan, or celecoxib acutely (3 days) chronically weeks). Molecular pathways mediating effects CsA on were studied in cultured macula densa cells. Results Pharmacological siRNA-mediated cells enhanced expression via p38 mitogen-activated protein kinase NF-kB signalling, whereas angiotensin II abolished these Acute chronic administration rats led activation along with reduced cortical expression, creatinine clearance fractional excretion. Evaluation major distal salt transporters, NKCC2 NCC, showed increased levels their activating phosphorylation upon CsA. Concomitant candesartan treatment blunted completely normalized functional parameters at long term. Celecoxib prevented candesartan-induced improvements Conclusion Suppression results from activation, which overrides cell-autonomous, COX-2-stimulatory inhibition. Angiotensin antagonism alleviates nephrotoxicity COX-2-dependent normalization