Synthesis and secretion of renin in mice with induced genetic mutations

Abstract

The juxtaglomerular (JG) cell product renin is rate limiting in the generation of the bioactive octapeptide angiotensin II. Rates of synthesis and secretion of the aspartyl protease renin by JG cells are controlled by multiple afferent and efferent pathways originating in the CNS, cardiovascular system, and kidneys, and making critical contributions to the maintenance of extracellular fluid volume and arterial blood pressure. Since both excesses and deficits of angiotensin II have deleterious effects, it is not surprising that control of renin is secured by a complex system of feedforward and feedback relationships. Mice with genetic alterations have contributed to a better understanding of the networks controlling renin synthesis and secretion. Essential input for the setting of basal renin generation rates is provided by β-adrenergic receptors acting through cyclic adenosine monophosphate, the primary intracellular activation mechanism for renin mRNA generation. Other major control mechanisms include COX-2 and nNOS affecting renin through PGE2, PGI2, and nitric oxide. Angiotensin II provides strong negative feedback inhibition of renin synthesis, largely an indirect effect mediated by baroreceptor and macula densa inputs. Adenosine appears to be a dominant factor in the inhibitory arms of the baroreceptor and macula densa mechanisms. Targeted gene mutations have also shed light on a number of novel aspects related to renin processing and the regulation of renin synthesis and secretion.

Fig 1

Schematic overview of the majority of genetic targets discussed in this review and their effects on renin release. Oval indicates a representative JG cell and effects on renin release are indicated by arrows with solid arrows delineating direct effects (or stimulatory effects with positive deflections) and broken arrows indicating inverse effects (or inhibitory effects with positive deflections). Pathways with an even number of broken arrows (zero or two) are stimulatory and pathways with an uneven number of broken arrows are inhibitory.

Fig. 2

Angiotensin II feedback inhibition of renin synthesis and secretion is mediated by AT1 receptors on both JG cells and on macula densa cells. Activation of JG cell receptors directly inhibits renin whereas activation of macula densa cell receptors (perhaps also of TAL and VSMC receptors) inhibits renin indirectly through downregulation of COX-2 and nNOS. Feedback inhibition by angiotensin II is not necessarily symmetrical: reductions of angiotensin II levels rely more exclusively on the indirect pathways than increases of angiotensin II. Solid arrows denote direct relationships or positive effects whereas broken arrows denote inverse relationships or negative effects. TAL: thick ascending limb of Henle's loop; VSMC: vascular smooth muscle cells; PDE3: phosphodiesterase 3; AC5/6: adenylyl cyclase 5 or 6.

Fig. 3

Relationship between basal plasma renin concentration (PRC) and the increase (Δ) of PRC caused by intraperitoneal injection of 40 mg/kg furosemide. Each symbol is the mean value of 5-10 measurements of PRC in wild type (black dots) and various mutant mouse models (open circles; mutants are used to extend the limited range of basal PRC in wild type to the higher values of NKCC1-/- and the lower values of the other mutant strains). Data are taken from references ^{, , , ,} .