Role of the soluble (pro)renin receptor in obstructive kidney disease

The (pro)renin receptor (PRR) is a multifunctional protein essential for nephron development and renal function. Cleavage of the extracellular domain of the PRR yields a soluble fragment, soluble PRR (sPRR), which has been implicated in blood pressure regulation and kidney disease. In this study, we examined whether loss of sPRR confers protection in obstructive kidney disease. Using CRISPR-Cas9, we developed a mouse with site directed mutagenesis of the PRR cleavage site preventing the formation of sPRR. Male mutant sPRR mice and littermate WTs were subjected to sham surgery, unilateral ureteral obstruction (UUO, 3 days of obstruction), or unilateral ureteral obstruction-release (UUOR, 3 days of obstruction followed by 28 days of recovery). Kidneys were assessed for injury, inflammation, and fibrosis using RT-PCR, Western blot, histology, and functional measures. In the UUO model, WT mice exhibited significant increases in gene expression of tubular injury ( Havcr1), fibrosis ( FN1, Col1a1), and inflammation ( Ccl2) compared to sham WT mice. In contrast, mutant sPRR mice with UUO had reduced expression of Havcr1, FN1, and Ccl2 relative to UUO or sham WT mice. In the UUOR model, WT mice with UUOR displayed elevated expression of Havcr1, Col1a1, Col3a1 and FN1, indicating progressive fibrosis. Mutant sPRR mice showed a trend toward reduced Col13a1 expression and collagen deposition by histology. GFR and BUN were unchanged across groups, consistent with functional compensation by the contralateral kidney. Loss of sPRR reduces tubular injury, inflammation, and fibrosis in UUO with more modest effects in UUOR.