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 PGE2 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.

Fluorescent reporter mice, Juxtaglomerular apparatus, Macula densa, Prorenin receptor, Renin,
American Journal of Physiology - Renal Fluid and Electrolyte Physiology
Erasmus MC: University Medical Center Rotterdam

Riquier-Brison, A.D.M. (Anne D. M.), Sipos, A. (Arnold), Prókai, Á. (Ágnes), Vargas, S.L. (Sarah L.), Toma, L. (Lldikó), Meer, E.J. (Elliott J.), … Peti-Peterdi, J. (János). (2018). The macula densa prorenin receptor is essential in renin release and blood pressure control. American Journal of Physiology - Renal Fluid and Electrolyte Physiology, 315(3), F521–F534. doi:10.1152/ajprenal.00029.2018