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Background: The (pro)renin receptor (PRR) is a transmembrane protein that plays an important role in how the kidney nephrons develop and function. When the extracellular portion of PRR is cleaved, the soluble (pro)renin receptor (sPRR) is formed. Patients with chronic kidney disease have high plasma sPRR levels. We investigated whether loss of sPRR is protective in aristolochic acid (AA) induced kidney disease.

Methods: A mutant sPRR mouse was developed using CRISPR-Cas9 by mutating the cleavage site of PRR. Male mutant sPRR mice (n=6) and their littermate controls (n=6) were given intraperitoneal injections of AA adjusted to their body weight for a dosage of 1.5 mg/kg, given every day, for a total of 4 consecutive days. Male littermate controls (n=5) were given a vehicle volume (DMSO) instead of AA. Metabolic cage studies were done on days 8-9 and GFR was measured on days 10-14. Urine assays were done to detect the kidney injury molecule (KIM-1) and albumin. The kidneys were harvested on day 16 and were examined for tubular damage (KIM-1) and fibrosis (Collagen-I, Collagen-III, Fibronectin-I) using qRT-PCR. Plasma assays were done to assess sPRR and BUN. One-way ANOVA was used to determine differences between the groups.

Results: Mutant sPRR mice had a lower body weight compared to both vehicle and drug controls (p<0.0001). AA injections resulted in an increase in KW/BW in both the AA control and the AA mutant sPRR (p<0.005, p<0.05), not indicating an improvement with the loss of sPRR. Urine albumin excretion and urine KIM-1 were elevated in both AA-treated groups (p<0.005, p<0.005) compared to the vehicle control. There was no significant reduction in these markers between control and mutant sPRR mice. There was no significant difference in GFR between the 3 groups. The gene expression of kidney injury and fibrosis markers was slightly elevated in both AA groups, but there was no statistical significance.

Conclusion: The absence of the sPRR did not significantly improve the markers of kidney injury in aristolochic acid-induced chronic kidney disease.