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Title: Deficiency of soluble (pro)renin receptor in aristolochic acid induced chronic kidney disease

Background: Aristolochic acid, a toxin found in the Balkan diet and traditional Chinese medicine, is implicated in chronic kidney disease (CKD). The soluble (pro)renin receptor (sPRR) is a cleaved product of the transmembrane protein, responsible for regulating blood pressure and kidney function. sPRR has been implicated in kidney fibrosis, a key indicator of chronic kidney disease. In this study, we investigated whether partial loss of sPRR would be protective in CKD in female mice.

Methods: A mouse model with mutation in the PRR cleavage site was created using CRISPR-Cas9 so that no sPRR is formed. Female mutant mice have reduced (~50%) sPRR levels as the PRR is on the X chromosome. Mutant sPRR mice and their littermate controls aged 7-12 months received injections of aristolochic acid (AA) or vehicle for 4 consecutive days. Mice were then placed into metabolic cages on days 8-9, GFR measured on days 15-16 and mice sacrificed on day 21. Kidney function was measured using ELISAs, RT-PCR and histology. Differences between groups were tested using one-way ANOVA.

Results: Female mutant sPRR mice had significantly lower plasma sPRR levels and similar body weight and kidney weight compared to controls. GFR, urinary excretion of KIM-1 and albumin were higher in the AA treated mice compared to vehicle treated mice with no significant differences between AA treated control and mutant sPRR mice. When compared to both control groups, BUN concentration in mutant sPRR mice was modestly higher. Finally, RTPCR was run on all 3 groups to compare kidney gene expression of collagen 1, collagen 3, KIM-1, and fibronectin. Compared to control mice treated with the vehicle, all 4 markers were elevated in AA-treated mice with a trend toward lower expression in the mutant sPRR mice, despite not reaching statistical significance.

Conclusion: The partial loss of sPRR did not protect the female mice from developing CKD.