Enhanced lipoxygenase/LTD4 signaling accounts for the exaggerated hypertensive and nephrotoxic effects of cyclosporine plus indomethacin in rats

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. Graphical abstract
Source: Biomedicine and Pharmacotherapy - Category: Drugs & Pharmacology Source Type: research