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Cyclosporine A induces Endothelin‐Converting Enzyme (ECE)‐1: Studies in‐vivo and in‐vitro

Abstract Aim

Cyclosporine A (CsA) induces renal vasoconstriction and hypoxia and enhances the expression of endothelin-1 (ET-1) pro-hormone (pre-pro ET-1), plausibly leading to a feed-forward loop of renal vasoconstriction, hypoxia, and enhanced synthesis of the potent vasoconstrictor ET-1. Endothelin converting enzyme (ECE)-1 cleaves big endothelin to generate endothelin (ET)-1 and is up-regulated by hypoxia via hypoxia-inducible factor (HIF). We hypothesized that in addition to the direct induction of ET-1 synthesis, CsA might also intensify renal ECE-1expression, thus contributing to enhanced ET-1 synthesis following CsA.


CsA was administered to Sprague Dawley rats (120 mg/kg/SC) for 4 days and renal HIF and ECE-1 expression were assessed with western blots and immunostaining. Human umbilical vein endothelial cells (HUVEC) and proximal tubular cell line (HK-2) were subjected to CsA and ECE-1 induction was evaluated using real-time mRNA PCR and western blots.


CsA intensified renal parenchymal ECE-1 expression in the rat kidney, particularly in distal nephron segments, along with renal hypoxia (detected by pimonidazole adducts) and HIF expression, in line with our recent observations showing episodic hypoxia in mice subjected to CsA. Furthermore, in cultured normoxic HUVEC and HK-2 cells, CsA dose-dependently induced both pre-pro-ET-1 and ECE-1 mRNA and protein expression, with enhanced ET-1generation.


CsA induces ECE-1 via both hypoxic and non-hypoxic pathways. ECE-1 may contribute to increased renal ET-1 generation following CsA, participating in a feed-forward loop of renal parenchymal hypoxia and ET synthesis.

This article is protected by copyright. All rights reserved.

Authors:   Samuel N. Heyman, Zaid Abassi, Christian Rosenberger, Hiba Yaseen, Galia Skarjinski, Ahuva Shina, Susanne Mathia, Natalia Krits, Mogher Khamaisi
Journal:   Acta Physiologica
Year:   2018
Pages:   n/a
DOI:   10.1111/apha.13033
Publication date:   13-Jan-2018
Facts, background information, dossiers
  • immunostaining
  • endothelial cells
  • copyright
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