PKC-delta mediates mineralocorticoid receptor activation by angiotensin II to modulate smooth muscle cell function.

PKC-delta mediates mineralocorticoid receptor activation by angiotensin II to modulate smooth muscle cell function. Endocrinology. 2019 Aug 02;: Authors: Lu Q, Davel AP, McGraw AP, Rao SP, Newfell BG, Jaffe IZ Abstract Angiotensin II (AngII) and the mineralocorticoid receptor(MR) ligand aldosterone, both contribute to cardiovascular disorders, including hypertension and adverse vascular remodeling.We previously demonstrated that AngII activates MR-mediated gene transcription in human vascular smooth muscle cells(SMC) yet the mechanism and the impact on SMC function are unknown.Using a MR responsive element-driven transcriptional reporter assay, we confirm that AngII induces MR transcriptional activity in multiple vascular SMC and endothelial cells, but not in Cos1 nor HEK293 cells.AngII activation of MR was blocked by the MR-antagonists spironolactone or eplerenone and the protein kinase C-δ(PKCδ)-inhibitor rottlerin, implicating both in the mechanism.Similarly, siRNA knock down of PKCδ in SMC prevented AngII-mediated MR activation, while knocking down of MR blocked both aldosterone- and AngII-induced MR function.Co-immunoprecipitation studies reveal that endogenous MR and PKCδ form a complex in SMC that is enhanced by AngII treatment in association with increased serine phosphorylation of the MR N-terminus.AngII increased mRNA expression of the SMC-MR target gene, FKBP5 via a MR-responsive element in intron 5 of the FKBP5 gene.T...
Source: Endocrinology - Category: Endocrinology Authors: Tags: Endocrinology Source Type: research