The macula densa prorenin receptor is essential in renin release and blood pressure control

Abstract

The prorenin receptor (PRR) was originally proposed to be a member of the renin-angiotensin system (RAS); however, recent work questioned their association. The present paper describes a functional link between the PRR and RAS in the renal juxtaglomerular apparatus (JGA), a classic anatomical site of the RAS. PRR expression was found in the sensory cells of the JGA, the macula densa (MD), and immunohistochemistry-localized PRR to the MD basolateral cell membrane in mouse, rat, and human kidneys. MD cell PRR activation led to MAP kinase ERK1/2 signaling and stimulation of PGE release, the classic pathway of MD-mediated renin release. Exogenous renin or prorenin added to the in vitro microperfused JGA-induced acute renin release, which was inhibited by removing the MD or by the administration of a PRR decoy peptide. To test the function of MD PRR in vivo, we established a new mouse model with inducible conditional knockout (cKO) of the PRR in MD cells based on neural nitric oxide synthase-driven Cre-lox recombination. Deletion of the MD PRR significantly reduced blood pressure and plasma renin. Challenging the RAS by low-salt diet + captopril treatment caused further significant reductions in blood pressure, renal renin, cyclooxygenase-2, and microsomal PGE synthase expression in cKO vs. wild-type mice. These results suggest that the MD PRR is essential in a novel JGA short-loop feedback mechanism, which is integrated within the classic MD mechanism to control renin synthesis and release and to maintain blood pressure.

Spatial Transcriptional Mapping of the Human Nephrogenic Program

“…The sex of embryos was not known. For Nos1 lineage-tracing, crosses were set as previously described (Riquier-Brison et al, 2018). In brief, Nos1Cre ERT2 (Nos1tm1.1(cre/ERT2)Zjh; Taniguchi et al, 2011) crossed with a conditional florescent protein reporter…”

The (pro)renin receptor: an emerging player in hypertension and metabolic syndrome

“…The macula densa PRR also appears to regulate BP and systemic renin release. 41 Using a combination of cell culture and in vivo studies, Riquier-Brison et al 41 demonstrated that the macula densa PRR amplifies renin/prorenin-stimulated renin release via ERK1/2 signaling in a short-loop feed forward mechanism. Consistent with this finding, mice with macula densa-specific PRR ablation have reduced BP and plasma renin levels; these effects were more prominent after treatment with a low-salt diet and RAS blockers.…”

“…Consistent with this finding, mice with macula densa-specific PRR ablation have reduced BP and plasma renin levels; these effects were more prominent after treatment with a low-salt diet and RAS blockers. 41 The renal PRR also may contribute to the development of hypertension in kidney disease. Mice heterozygous for PRR deletion in nephron progenitor cells (homozygous deletion leads to early neonatal death) have fewer glomeruli and altered glomerular basement membrane ultrastructure and experience develop hypertension at 2 months of age, 42 suggesting that early loss of PRR may be involved in developmental programming of hypertension.…”

Return of the (pro)renin receptor: a novel role in macula densa signaling

“…However, recent studies have challenged this notion and propose a RAS-independent role for the PRR (4, 10) involving lysosomal function and Wnt-␤ catenin pathway. Using a systematic approach, the current study provides unequivocal evidence for PRR function within the RAS and presents a novel feed-forward mechanism by which macula densa PRR regulates renin release from the juxta-glomerular cells (8).…”

“…The prevailing view of macula densa signaling is that a fall in tubular fluid salt content activates several intracellular mechanisms, including cyclooxygenase-2 (COX2), microsomal prostaglandin E synthase (mPGES), neuronal nitric oxide synthase (nNOS), extracellular signal-regulated kinase-1/2 (ERK1/2), and mitogen-activated protein kinase (MAPK) pathways, leading to basolateral secretion of prostaglandin E 2 (PGE 2 ) and nitric oxide (NO), which, in turn, stimulate renin release from the neighboring juxtaglomerular cells (2). In a recent issue of this journal, Riquier-Brison et al (8) demonstrate a novel perspective on macula densa signaling of renin release and consequent blood pressure regulation via the (pro)renin receptor (PRR).…”