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Cyclosporine A induces endothelin‐converting enzyme‐1: Studies in vivo and in vitro
Author(s) -
Heyman S. N.,
Abassi Z.,
Rosenberger C.,
Yaseen H.,
Skarjinski G.,
Shina A.,
Mathia S.,
Krits N.,
Khamaisi M.
Publication year - 2018
Publication title -
acta physiologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 116
eISSN - 1748-1716
pISSN - 1748-1708
DOI - 10.1111/apha.13033
Subject(s) - endothelin 1 , endocrinology , endothelin receptor , kidney , hypoxia (environmental) , medicine , vasoconstriction , umbilical vein , biology , chemistry , in vitro , receptor , biochemistry , organic chemistry , oxygen
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 upregulated 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 ‐1 expression, thus contributing to enhanced ET ‐1 synthesis following CsA. Methods 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. Results Cyclosporine A 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 ‐1 generation. Conclusion 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.