Role of the soluble (pro)renin receptor in obstruction induced chronic kidney disease

Background: The (pro)renin receptor (PRR) is a multifunctional, transmembrane protein that is critical to nephron development and renal tubular function. In its cleaved form, the soluble (pro)renin receptor (sPRR) is important in blood pressure regulation and kidney function. We previously reported that loss of sPRR attenuated angiotensin-II induced hypertension and adenine induced kidney disease. In this study, we investigated whether loss of the sPRR is protective in obstructive chronic kidney disease (CKD). Methods: Using CRISP-Cas9, we developed a mouse model with site directed mutagenesis of the PRR cleavage site. Male, 5-7 month-old, mutant sPRR mice and littermate controls were subjected to sham or unilateral ureteral obstruction-release (UUOR) procedure. The UUOR procedure involved obstruction of the left ureter for 72 hours, followed by release and evaluation of kidney injury and fibrosis 28-days later. Obstructed kidney was examined for tubular injury (kidney injury marker-1, KIM-1) and fibrosis markers (collagen-I and fibronectin) using RT-PCR. Histology using Trichrome, PAS staining, and Sirius Red staining was used to assess kidney injury. GFR and BUN were also measured at the end of the study. Two-way ANOVA was used to examine differences among the groups. Results: Compared to controls, male mutant sPRR mice had markedly lower plasma sPRR levels (control: 24.4 ± 5.0 vs 0.3 ± 0.05 ng/ml, p value <0.001). Compared to control mice subjected to sham procedure (N=4), the control UUOR mice (N=6) had 5.3 ± 1.6 fold increase in collagen-I expression while the mutant UUOR mice (N=6) had 2.2 ± 0.5 fold increase; a 2.3 ± 0.3 fold increase in fibronectin while mutant UUOR had 1.5 ± 0.4 fold increase; and 66.4 ± 14.9 fold increase in KIM-1 while mutant UUOR 48.9 ± 20.1 fold increase (ANOVA p=0.05 by genotype & surgery, p<0.01 by fibrosis marker and interaction). Post-hoc analyses of multiple comparisons showed that control UUOR had higher KIM-1 compared to control sham (p<0.05) or mutant UUOR (p=0.05). Kidney histology by PAS and Trichrome staining showed increased inflammation and tubular damage in the control UUOR group compared to control sham and mutant sPRR mice. No differences in BUN or GFR were observed comparing sham versus UUOR in control or mutant sPRR mice which is expected as the contralateral kidney likely compensated for loss of kidney function in the obstructed kidney. Conclusion: The loss of the sPRR may be protective in mice with obstructive kidney disease. Further studies are planned to delineate the molecular mechanisms by which loss of sPRR affords kidney protection. R01DK133271 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.