engleski

Big endotehelin-1 stimulates 1, 2 - diacylglycerol generation in the rat proximal tubule independently from the conversion into endothelin-1

Endothelin-1 (ET-1) is formed from its precursor big ET-1by the action of ednothelin-converting enzyme (ECE). Unlike the renal vascular effects of big ET-1, tubular responses to big ET-1 in the rat kidney were demonstrated to be only partially sensitive to an ECE inhibitor phosphoramidon (Pho). In our previous study we demonstrated in the rat proximal tubule (PT) ET-dependent stimulation of phospholipase C trough the ET(B) receptors in the brush-border membrane (BBM), and ET(C) receptors in the basolateral membrane. In the present study the relationship between the functional response to big ET-1 and its conversion to the ET-1 in rat PT was assessed. 10 min incubation of renal cortical slices with 10(-7) M big ET-1 resulted in 712+96 fmol ET-1/mg tissue. In the slice pretreated with Pho 10(-4) M, tissue ET-1 content following 10 min incubation with 10(-7) M big ET-1 was reduced (309+12 fmol ET-1/mg tissue, p<0.05 vs. big ET-1 + Pho), demonstration the presence and the efficacy of inhibition of the ECE. Following incubation of renal cortical slices with big ET-1, dose- and time-dependent increment in 1, 2 -diacylglycerol (DAG) was observed in BBM. There was no increment in DAG in response to big ET-1 in BLM. Following 7 min incubation of renal coritcal slices with 10(-7) M big endothelin-1, DAG concentration in BBM increased from 317+6 pmol/mg prot. (p<0.001). This increment in DAG in the BBM was insensitive to the pretreatment with 10(-4) M Pho (438+6 pmol/mg prot., n.s. compared to big ET-1 alone). We conclude that in the rat PT, big ET-1 dependent signalling may occur independently from its prior enyzmatic conversion into ET-1. BBM may probably be the site of big ET-1-sensitive receptors.

big endothelin-1; endothelin-1; 1; 2-diacylglycerol; rat proximal tubule

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