Endothelin-1-induced activation of rat renal pelvic contractions depends on cyclooxygenase-1 and Rho kinase

Abstract

Upper urinary tract peristalsis is generated in the proximal renal pelvis that connects to the renal parenchyma at the pelvis-kidney junction. It may be exposed to the high renal endothelin-1 (ET-1) concentrations. Dietary NaCl restriction increases renal pelvic ETA receptor expression. We investigated the contribution of ETA and ETB receptors to ET-1-stimulated rat renal pelvic contractions and whether the sensitivity of renal pelvic contractile activity to ET-1 stimulation increases with dietary NaCl restriction. We tested whether ET-1-induced contractile activity depends on cyclooxygenase (COX)-1 or -2 and to what extent spontaneous as well as agonist-induced peristalsis depends on Rho kinases (ROCK). Contractions of isolated renal pelvises were investigated by myography. ET-1 concentration-dependently increased pelvic contractile activity up to 400% of basal activity. ETA but not ETB receptor blockade inhibited ET-1-induced pelvic contractions. Basal and ET-1-stimulated contractions were similar in renal pelvises from rats on a high-NaCl diet or on a NaCl-deficient diet. COX-1 inhibition reduced spontaneous and almost completely blocked the ET-1-induced pelvic contractions. ROCK inhibition reduced spontaneous and ET-1 stimulated pelvic contractile activity by 90%. RT-PCR revealed that both ROCK isoenzymes are present in the renal pelvic wall. Western blot analyses did not show increased phosphorylation of ROCK substrates myosin phosphatase target subunit 1, ezrin, radixin, and moesin in ET-1-treated isolated renal pelvises. ET-1 is a powerful ETA receptor-dependent activator of renal pelvic contractions. COX-1 and ROCK activity are required for the ET-1 effects on pelvic contractions, which are not significantly affected by dietary NaCl intake.