Endothelin ET_A receptor/lipid peroxides/COX‐2/TGF‐β1 signalling underlies aggravated nephrotoxicity caused by cyclosporine plus indomethacin in rats

Abstract

BACKGROUND AND PURPOSECyclosporine (CSA) and non-steroidal anti-inflammatory drugs (NSAIDs) are co-prescribed for some arthritic conditions. We tested the hypothesis that this combined regimen elicits exaggerated nephrotoxicity in rats via the up-regulation of endothelin (ET) receptor signalling. EXPERIMENTAL APPROACHThe effects of a 10 day treatment with CSA (20 mg·kg ) or their combination on renal biochemical, inflammatory, oxidative and structural profiles were assessed. The roles of ETA receptor and COX-2 pathways in the interaction were evaluated. KEY RESULTSOral treatment with CSA or indomethacin elevated serum urea and creatinine, caused renal tubular atrophy and interstitial fibrosis, increased renal TGF-β1, and reduced immunohistochemical expressions of ETA receptors and COX-2. CSA, but not indomethacin, increased renal ET-1, the lipid peroxidation product malondialdehyde (MDA) and GSH activity. Compared with individual treatments, simultaneous CSA/indomethacin exposure caused: (i) greater elevations in serum creatinine and renal MDA; (ii) loss of the compensatory increase in GSH; (iii) renal infiltration of inflammatory cells and worsening of fibrotic and necrotic profiles; and (iv) increased renal ET-1 and decreased ETA receptor and COX-2 expressions. Blockade of ETA receptors by atrasentan ameliorated the biochemical, structural, inflammatory and oxidative abnormalities caused by the CSA/indomethacin regimen. Furthermore, atrasentan partly reversed the CSA/indomethacin-evoked reductions in the expression of ETA receptor and COX-2 protein. CONCLUSIONS AND IMPLICATIONSThe exaggerated oxidative insult and associated dysregulation of the ETA receptor/COX-2/TGF-β1 signalling might account for the aggravated nephrotoxicity caused by the CSA/indomethacin regimen. The potential renoprotective effect of ETA receptor antagonism might be exploited therapeutically.

Molecular Biomarkers as Predictors for Biliary Complications Following Liver Transplantation. A Prospective Study

“…Cyclosporine enhances the generation of endothelin-1 [17], which intensifies vascular derangements and promotes the synthesis and activation of profibrotic molecules such as TGF-β1 and adhesion molecules. Similar to the reported nephrotoxicity due to increased interstitial fibrosis scores [18], there was a significantly higher serum Table I. Relative levels of endothelin 1 at days 7 and 30 following LT. Endothelin-1 levels in plasma and hepatic tissue are elevated in human patients with chronic hepatitis or cirrhosis, and this increase is proportional to the severity of liver disease, thus contributing to portal hypertension [19,20].…”

Opposite Modulatory Effects of Selective and Non‐Selective Cyclooxygenase Inhibition on Cardiovascular and Autonomic Consequences of Cyclosporine in Female Rats

“…Celecoxib also elicits a potent vasodilator capacity in human mesenteric arteries [50]. Reports from our laboratory and others highlighted favourable effects for COX-2 inhibition on myocardial ischaemia [51,52] and vasculotoxicity [20,21].…”

“…Previous reports from our laboratory demonstrated a protective effect for celecoxib, but not indomethacin, against the hypertensive and nephrotoxic actions induced by chronic CSA administration in male rats via the modulation of endothelin receptor expression [20,21]. The aim of the current study was to clarify the acute haemodynamic interaction between CSA and NSAIDs with different COX selectivity in female rats.…”

“…We also reported that the decreases in COX‐2 expression caused by CSA were ameliorated after concurrent treatment with celecoxib but not indomethacin . The negative modulation of the TGF‐β1/IL‐2 pathway appears to mediate the reversing action of celecoxib on CSA‐induced COX‐2 up‐regulation . Notably, although COX‐2 and its prostanoid products are generally considered as pro‐inflammatory mediators , evidence suggests that they also exhibit vasodilator and antifibrotic properties .…”

“…The ameliorating effect of celecoxib on CSA hypertension was accounted for by its ability to reverse the associated increases and decreases in vascular endothelin ETA and ETB receptor expressions, respectively [20]. We also reported that the decreases in COX-2 expression caused by CSA were ameliorated after concurrent treatment with celecoxib but not indomethacin [21,22]. The negative modulation of the TGF-b1/IL-2 pathway appears to mediate the reversing action of celecoxib on CSA-induced COX-2 up-regulation [21,22].…”