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 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.
Subject(s)
Blood Pressure , Juxtaglomerular Apparatus/enzymology , Proton-Translocating ATPases/metabolism , Receptors, Cell Surface/metabolism , Renin-Angiotensin System , Renin/metabolism , Vacuolar Proton-Translocating ATPases/metabolism , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Biosensing Techniques , Blood Pressure/drug effects , Captopril/pharmacology , Cyclooxygenase 2/metabolism , Diet, Sodium-Restricted , Dinoprostone/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , HEK293 Cells , Humans , Juxtaglomerular Apparatus/drug effects , Male , Mice, Inbred C57BL , Mice, Knockout , Prostaglandin-E Synthases/metabolism , Proton-Translocating ATPases/deficiency , Proton-Translocating ATPases/genetics , Rats, Sprague-Dawley , Receptors, Cell Surface/deficiency , Receptors, Cell Surface/genetics , Renin-Angiotensin System/drug effects , Secretory Pathway , Signal Transduction , Vacuolar Proton-Translocating ATPases/genetics , Prorenin ReceptorABSTRACT
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has disrupted health care globally with dramatic impacts on cancer care delivery in addition to adverse economic and psychological effects. This study examined impacts of the SARS-CoV-2 pandemic on young adult colorectal cancer (CRC) survivors diagnosed age 18-39 years. Nearly 40% reported delays in cancer-related care, loss of income, and poorer mental health during the pandemic. Impacts were greater for survivors aged 20-29 years, with nearly 60% reporting cancer care delays and 53% experiencing income loss. Such impacts may result in detrimental downstream outcomes for young CRC survivors, requiring specific support, resources, and continued monitoring.