Multiple Cross Talk between Angiotensin II, Bradykinin, and Insulin Signaling in the Cortical Thick Ascending Limb of Rat Kidney

Abstract

Cortical thick ascending limb (CTAL) naturally expresses the angiotensin II (AngII) receptor type 1A (AT(1)-R), the bradykinin (BK) receptor type 2 (B(2)-R), and the insulin receptor. This segment is made of a single morphologically distinct cell type. AngII and BK are involved in same transduction pathways but differ markedly in their physiological actions on Na(+) transport. Besides, the insulin signaling intersects with those of AngII and BK at multiple levels and especially by stimulation on Na(+) reabsorption. Thus, the CTAL is a biologically suitable model to study the cross talk between G protein-coupled receptors or G protein-coupled receptors and receptor tyrosine kinase. In this work, the cross talks between AngII, BK, and insulin signaling are studied in rat CTAL by measuring changes in [Ca(2+)](i). We show that BK exerts negative modulatory effects on AngII-induced [Ca(2+)](i) responses dependent on tyrosine kinase and MAPK pathways. Moreover, in the presence of BK, AngII-induced Na(+) transport is suppressed. These effects suggest an interaction between AT(1)-R and B(2)-R. We show a positive interaction between the insulin receptor and the AT(1)-R through a protein kinase A-dependent mechanism that involves MAPK cascade, leading to the stimulation of the Ca(2+) influx induced by AngII. The presence of such interactions brings additional arguments for a complex and fine regulation of CTAL functions and puts forward the potentially beneficial effect of BK across this segment, in case of hyperinsulinemia or insulin resistance, by its negative feedback on AngII actions.