Novel mechanisms for the control of renin synthesis and release

Abstract

Renin is the key regulated step in the enzymatic cascade that leads to angiotensin generation and the control of blood pressure and fluid/electrolyte homeostasis. In the adult unstressed animal, renin is synthesized and released by renal juxtaglomerular cells. However, when homeostasis is threatened, the number of cells that express and release renin increases and extends beyond the juxtaglomerular area; the result is an increase in circulating renin and the reestablishment of homeostasis. The increase in the number of renin cells, a process termed recruitment, is achieved by dedifferentiation and re-expression of renin in cells derived from the renin lineage. The mechanisms that regulate the related processes of reacquisition of the renin phenotype, renin synthesis, and renin release are beginning to be understood. Numerous studies point to cAMP as a central common factor for the regulation of renin phenotype. In addition, we are seeing the emergence of gap junctions and microRNAs as new and promising avenues for a more complete understanding of the complex regulation of the renin cell.

Fig. 1

Simplified scheme of the cAMP pathway and the regulation of renin synthesis and release. Activation of a G protein–coupled receptor (GPCR) by its ligand results in a conformational change that is transmitted to a heterotrimeric G protein complex. The Gsα subunit, through conversion of guanosine triphosphate (GTP) into guanosine diphosphate (GDP), is released from the complex and activates the adenylyl cyclase, which in turn converts adenosine triphosphate (ATP) into the second messenger cAMP (red dots). cAMP binding to the regulatory subunits (R) of protein kinase A (PKA) results in the release of the catalytic subunits (C) that, in the nucleus, phosphorylate the cAMP-responsive element binding protein (CREB). Phosphorylated CREB recruits the coactivators CBP and p300. Upon binding to the cAMP-responsive element (CRE) in the enhancer region of the renin promoter, this complex switches on the transcription of renin mRNA. Posttranscriptional regulation at the 3′ untranslated region (UTR) occurs by binding proteins that increase renin mRNA stability, and perhaps by microRNAs (miRNA), which repress renin translation and/or degrade renin mRNA. cAMP also stimulates renin release (dashed arrow). Degradation of cAMP occurs by the action of a phosphodiesterase (PDE) that converts it to AMP. The modulating effects of calcium described in the text are omitted for clarity. GJ gap junction, MEJ myoendothelial junction, Pol II polymerase II