Enhanced lipoxygenase/LTD4 signaling accounts for the exaggerated hypertensive and nephrotoxic effects of cyclosporine plus indomethacin in rats
2018
Abstract The combined use of cyclosporine (CSA) and nonsteroidal antiinflammatory drugs (NSAIDs) causes exaggerated rises in systolic blood pressure (SBP) and nephrotoxicity. We examined whether these influences relate to the arachidonate/5-lipoxygenase (LOX) pathway. Rats were treated with CSA (20 mg kg −1 day −1 ), indomethacin (5 mg kg −1 day −1 ), or their combination for 10 days. Changes in SBP and renal biochemical/histopathological characteristics along with leukotriene levels were determined in rats treated with or without LT receptor antagonists. CSA or indomethacin caused: (i) renal tubular atrophy and interstitial fibrosis, (ii) increases in serum creatinine, blood urea nitrogen (BUN), and renal LTD4, LTB4, TNF-α, TGF-β1, and caspase-3, and (iii) decreases in renal PGE2 and total antioxidant capacity (TAC). SBP measured by tail-cuff plethysmography was increased by CSA but not indomethacin. These effects were mostly intensified in rats treated with CSA plus indomethacin. The co-treatment with montelukast (cysteinyl LT receptor blocker), but not ONO-4057 (LTB4 receptor blocker), ameliorated CSA/indomethacin-evoked hypertension, renal structural/biochemical deterioration, and LTD4 levels. Moreover, montelukast exhibited a greater capacity in reversing inflammatory, oxidative, apoptotic, and fibrotic abnormalities induced by CSA/indomethacin. Overall, lipoxygenase/LTD4 upregulation contributes to the exaggerated hypertension and nephrotoxicity caused by CSA/indomethacin. The therapeutic potential of cysteinyl LT receptor antagonism in rectifying CSA/NSAIDs-evoked anomalies is warranted.
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