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The effect of big endothelin‐1 in the proximal tubule of the rat kidney
Author(s) -
BearaLasić Lada,
Knotek Mladen,
Čejvan Kenan,
Jakšić Ozren,
Lasić Zoran,
Skorić Boško,
Brkljačić Vera,
Banfić Hrvoje
Publication year - 1997
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0700956
Subject(s) - phosphoramidon , medicine , endocrinology , endothelin receptor , chemistry , kidney , diacylglycerol kinase , endothelin 3 , endothelins , biology , receptor , enzyme , biochemistry , protein kinase c
1 An obligatory step in the biosynthesis of endothelin‐1 (ET‐1) is the conversion of its inactive precursor, big ET‐1, into the mature form by the action of specific, phosphoramidon‐sensitive, endothelin converting enzyme(s) (ECE). Disparate effects of big ET‐1 and ET‐1 on renal tubule function suggest that big ET‐1 might directly influence renal tubule function. Therefore, the role of the enzymatic conversion of big ET‐1 into ET‐1 in eliciting the functional response (generation of 1,2‐diacylglycerol) to big ET‐1 was studied in the rat proximal tubules. 2 In renal cortical slices incubated with big ET‐1, pretreatment with phosphoramidon (an ECE inhibitor) reduced tissue immunoreactive ET‐1 to a level similar to that of cortical tissue not exposed to big ET‐1. This confirms the presence and effectiveness of ECE inhibition by phosphoramidon. 3 In freshly isolated proximal tubule cells, big ET‐1 stimulated the generation of 1,2‐diacylglycerol (DAG) in a time‐and dose‐dependent manner. Neither phosphoramidon nor chymostatin, a chymase inhibitor, influenced the generation of DAG evoked by big ET‐1. 4 Big ET‐1‐dependent synthesis of DAG was found in the brush‐border membrane. It was unaffected by BQ123, an ET A receptor antagonist, but was blocked by bosentan, an ET A B ‐nonselective endothelin receptor antagonist. 5 These results suggest that the proximal tubule is a site for the direct effect of big ET‐1 in the rat kidney. The effect of big ET‐1 is confined to the brush‐border membrane of the proximal tubule, which may be the site of big ET‐1‐sensitive receptors.