Human Soluble Prorenin Receptor Expressed in Mouse Renal Collecting Duct Show Sex-Specific Effect on Cardiorenal Function.

Soluble prorenin receptor (sPRR), a component of the renin angiotensin system (RAS), has been identified as a plasma biomarker for hypertension and cardiovascular diseases in humans. Despite studies showing that sPRR in kidney is produced by renal collecting duct (CD) tubular cells, its biological actions modulating cardiorenal function remains unknown. Therefore, this study aimed to create a new murine model to investigate how expressing human sPRR (HsPRR) in CD influence the intrarenal RAS status and renal hemodynamics in male and female mice fed a regular chow. CD-HsPRR mice were generated by breeding human sPRR-Myc-tag transgenic mice with transgenic mice expressing Hoxb7/Cre, which showed increased renal sPRR expression but unchanged circulating levels compared to CTL mice in both sexes. Plasma RAS levels were not influenced by the expression of HsPRR in CD as well. CD-HsPRR expression showed only in female littermates: 1) increased 24-hour blood pressure, due to elevated daytime mean and systolic values, 2) impaired blood pressure response to an acute dose of losartan and reduced chronic angiotensin II (AngII)-hypertension, 3) reduced ACE activity and Ang II content in renal cortex, 4) decreased GFR, with no changes in natriuresis and kaliuresis despite the upregulation of β-ENaC in renal cortex. Taken together, these data suggest that expression of HsPRR in CD could interact with Ang II type 1 receptor mediating a sex-specific, Ang II-independent renal dysfunction and pro-hypertensive phenotype.