Endothelin ETA Receptor/lipid Peroxides/COX-2/TGF-β1 Signalling Underlies Aggravated Nephrotoxicity Caused by Cyclosporine Plus Indomethacin in Rats

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2015 May 28

PMID 26013701

Citations 9

Authors

Maged W Helmy

Hanan M El-Gowelli

Rabab M Ali

Mahmoud M El-Mas

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: Cyclosporine (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 Approach: The effects of a 10 day treatment with CSA (20 mg · kg(-1) · day(-1)), indomethacin (5 mg · kg(-1) · day(-1)) 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 Results: Oral 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 Implications: The 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.

Citing Articles

Gestationally administered RAS modulators reprogram endotoxic cardiovascular and inflammatory profiles in adult male offspring of preeclamptic rats.

Abuiessa S, Helmy M, El-Gowelli H, El-Gowilly S, El-Mas M Naunyn Schmiedebergs Arch Pharmacol. 2024; 398(1):699-713.

PMID: 39046530 DOI: 10.1007/s00210-024-03305-2.

Suppression by central adenosine A3 receptors of the cholinergic defense against cardiovascular aberrations of sepsis: role of PI3K/MAPKs/NFκB signaling.

El-Naggar A, Helmy M, El-Gowilly S, El-Mas M Front Pharmacol. 2024; 15:1418981.

PMID: 38966542 PMC: 11222418. DOI: 10.3389/fphar.2024.1418981.

Adenosine A1 receptors of the medullary solitary tract arbitrate the nicotine counteraction of neuroinflammation and cardiovascular dysfunction in septic rats.

El-Naggar A, Helmy M, El-Gowilly S, El-Mas M Sci Rep. 2023; 13(1):17818.

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Montelukast potentiates the antiinflammatory effect of NSAIDs in the rat paw formalin model and simultaneously minimizes the risk of gastric damage.

Abdelhady S, Ali M, Al-Shafie T, Abdelmawgoud E, Yacout D, El-Mas M Inflamm Res. 2021; 70(9):981-992.

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Time and sex dependency of hemodynamic, renal, and survivability effects of endotoxemia in rats.

Wedn A, El-Gowilly S, El-Mas M Saudi Pharm J. 2020; 28(1):127-135.

PMID: 31933528 PMC: 6950976. DOI: 10.1016/j.jsps.2019.11.014.

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