Lack of the Prorenin Receptor in the Collecting Duct blunts the ENaC responses to Chronic Angiotensin II
Authors: Gonzalez Alexis A , Reverte‐Ribo Virginia , Katsurada Akemi , Rosales Carla B , Galatty Michael , McLellan Matthew , Gentile Oliver , Veiras Luciana C , Seth Dale M , Ichihara Atsuhiro , Mc Donough Alicia A , Mamenko Mykola , Pochynyuk Oleh M , Navar L Gabriel , Prieto Minolfa C 
Published: November 2023

The prorenin receptor (PRR) facilitates the conversion of angiotensinogen (AGT) to angiotensin (Ang) I by activating prorenin and enhancing renin activity. High circulating Ang II levels are associated with the development and progression of hypertension (HTN) and exert well‐known effects on the stimulation of aldosterone secretion and the activation of epithelial Na+ channels (ENaC). Ang II also increases Na+ reabsorption in the collecting duct (CD) of the kidney through a direct Ang II type 1 receptor (AT1R)‐dependent activation of ENaC. During pathological increases of intrarenal Ang II content, prorenin, renin, and PRR are augmented in the CD suggesting that PRR may contribute to intratubular Ang II formation. In the present study, we addressed the hypothesis that the CD‐derived PRR contributes to BP control by increasing intratubular Ang II formation and regulating Na+ transporters in the distal nephron segments. To address this hypothesis we generated a CD‐specific PRR knockout (CDPRR‐KO) mouse model to examine BP, sodium handling, distal nephron sodium transporters expresion, and functional activity of ENaC during basal conditions and chronic Ang II‐infusion. At basal conditions, there were no differences in body weight, food intake, or water intake between control and KO mice. However, KO mice showed fewer glomeruli and reduced kidney weight (P<0.05). Compared to floxed controls, CDPRR‐KO mice exibithed readuced MAP (71.5 ± 3.7 vs. 84.4 ± 1.3 mmHg, P<0.05) and lower urine osmolality (577 ± 56 vs. 939 ± 49 mOsmol/L, P<0.01). These changes were accompained by increases in fractional Na+ excretion (1.5 ± 0.4 vs. 0.9 ± 0.2 %, P<0.05), and urine flow (2.9 ± 0.4 vs. 1.1 ± 0.1 ml/day, P<0.05) but significantly decreased Ang II levels in urine (6.2 ± 2.2 vs. 9.6 ± 1.8 pg/h, P<0.05) compared to controls. After 14 days of Ang II infusion (400ng/kg/min), CDPRR‐KO mice showed attenuated elevations of SBP as compared to controls. By immunoblotting, no differences were found in α, β and γ ENaC subunits nor NCC expression at basal conditions. After chronic Ang II infusions total NCC, phosphorylated NCC (P‐S71), full length αENaC, and cleaved αENaC and γENaC were similarly elevated in abundance in the kidneys from both CDPRR‐KO and control mice. The ENaC activity (fNPo, functional ENaC expression and ENaC Po) examined in freshly isolated aldosterone‐sensitive micro‐dissected distal nephrons were similar in CDPRR‐KO and control mice. Chronic Ang II‐infusion increased ENaC activity in KO mice (1.1 ± 0.2 vs. 0.3 ± 0.1 fNPo), but the response was blunted in these mice due to reduced ENaC Po and ENaC active channels. These data provide a mechanistic explanation for the attenuation of BP response during chronic Ang II infusion in mice with cell‐type specific deletion of the PRR in the CD, in which a reduced catalytic activity of local available prorenin may lead to less intratubular Ang II formation and reduced ENaC Po and ENaC active channels.

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