Deletion of the Prorenin Receptor in the collecting duct impairs renal function and attenuates blood pressure in chronic angiotensin II‐infused mice
Authors: RIBO VIRGINIA REVERTE , Gogulamudi Venkateswara Reddy , Gonzalez Alexis A , Rosales Carla B , Gallaty Michael Royce , Castillo Alexander , Ichiara Atsuhiro , Navar L. Gabriel , Prieto Minolfa C 
Published: November 2023

The prorenin receptor (PRR), a specific receptor for renin and prorenin, is primarily expressed in the intercalated cells of the collecting duct (CD). The augmented expression of PRR in the kidneys of rodent models with experimental hypertension suggests a potential role of the PRR in the regulation of renal function; yet this remains undetermined. To examine the functional role of the PRR in the distal nephron on renal function, we generated mice with cell‐type specific deletion of the PRR in the CD. PRR is only expressed by the intercalated cells but not by the principal cells. To delete the PRR gene (Atp6ap2) from the CD (CDPRR‐KO), we used conditional floxed Atp6ap2 allele (Atp6ap2flox/flox) provided by Dr. Atsuhiro Ichihara (Japan), which were bred with transgenic mice for the Hoxb7 gene promoter driving expression of Cre‐recombinase (Hoxb7‐Cre). Renal functional studies were performed in control (CT, N=8) and CDPRR‐KO male (N=6) mice anesthetized with Inactin (100 mg/kg i.p) and then placed on a temperature‐regulated surgical table for continuous i.v infusion (0.003ml/min) with inutest, 20% sodium p‐aminohippurate (PAH), and 1% bovine serum albumin dissolved in isotonic saline. Renal function parameters were measured after a 60‐min stabilization period. Three 30‐min basal clearance collections were obtained. Mean arterial pressure (MAP) was continuously recorded, and data were averaged for each clearance period. In addition, urine flow (UV), inulin and PAH clearances, and urinary sodium and potassium excretion rates (UNaV and UKV, respectively) were measured. Blood samples were collected at the end of the third basal period. After euthanasia, both kidneys were removed and measured, weighed, and examined macro‐ and microscopically. Body Weight was similar in both KO and CT mice, but kidney weight was less in KO mice (0.299±0.042 g vs. 0.393±0.021 g) and glomerular number was also lower (35.80±2.65 glom/slide vs. 47.17±2.34 glom/kidney section; P<0.05). Renal papillae volume were decreased in KO compared with CT mice. KO mice exhibited greater urine flow (8.91±1.36 vs. 5.8±10.67 uL/min/Kw g) which was associated with a 38.5% lower in urine osmolarity (581±65 vs. 939±49 mmol/Kg). The KO mice also exhibited lower MAP (71±4 vs. 84±1 mmHg), GFR (0.54±0.06 vs. 0.89±0.12 ml/min/kw g) and urine sodium and potassium excretion rates (UNaV: 0.8±0.2 vs. 1.3±0.2 umol/min/kw g and UKV: 0.97±0.4 vs. 1.5±0.2 umol/min/kw g, respectively). RBF values did not differ from CT mice (5.2±0.8 vs. 6.5±1.0 ml/min/kw g). Sodium fractional excretion (FENa) was higher (P<0.05) in KO mice as compared to CT (1.55±0.36 vs. 0.89±0.16%). In response to 14 days of chronic Ang II infusion, 24‐h SBP values, measured by telemetry, were lower (P<0.05) in KO (N=4) than in CT mice (N=4) (126.6±2.3 vs.141.0±4.5 mmHg). These results indicate that cell‐type specific deletion of the PRR in the collecting duct impairs basal renal function, as well as attenuates the increases in arterial pressure during chronic Ang II‐infused mice.

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NIH‐NIDDK (RO1DK104375)