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.

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Keywords Fluorescent reporter mice, Juxtaglomerular apparatus, Macula densa, Prorenin receptor, Renin
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Journal American Journal of Physiology - Renal Fluid and Electrolyte Physiology
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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