The effect of big endothelin-1 in the proximal tubule of the rat kidney.
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 ETA receptor antagonist, but was blocked by bosentan, an ETA.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.[1]References
- The effect of big endothelin-1 in the proximal tubule of the rat kidney. Beara-Lasić, L., Knotek, M., Cejvan, K., Jaksić, O., Lasić, Z., Skorić, B., Brkljacić, V., Banfić, H. Br. J. Pharmacol. (1997) [Pubmed]
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