Renal injury leads to
chronic kidney disease, with which women are not only more likely to be diagnosed than men but have poorer outcomes as well. We have previously shown that expression of small
proline-rich region 2f (Sprr2f), a member of the small
proline-rich region (Sprr) gene family, is increased several hundredfold after renal injury using a unilateral
ureteral obstruction (UUO) mouse model. To better understand the role of Sprr2f in renal injury, we generated a Sprr2f knockout (Sprr2f-KO) mouse model using CRISPR-Cas9 technology. Sprr2f-KO female mice showed greater renal damage after UUO compared with wild-type (Sprr2f-WT) animals, as evidenced by higher
hydroxyproline levels and denser
collagen staining, indicating a protective role of Sprr2f during renal injury. Gene expression profiling by
RNA sequencing identified 162 genes whose expression levels were significantly different between day 0 and day 5 after UUO in Sprr2f-KO mice. Of the 162 genes, 121 genes were upregulated after UUO and enriched with those involved in oxidation-reduction, a phenomenon not observed in Sprr2f-WT animals, suggesting a protective role of Sprr2f in UUO through defense against oxidative damage. Consistently, bilateral
ischemia-reperfusion injury resulted in higher serum blood
urea nitrogen levels and higher tissue
reactive oxygen species in Sprr2f-KO compared with Sprr2f-WT female mice. Moreover, cultured renal epithelial cells from Sprr2f-KO female mice showed lower viability after oxidative damage induced by
menadione compared with Sprr2f-WT cells that could be rescued by supplementation with
reduced glutathione, suggesting that Sprr2f induction after renal damage acts as a defense against
reactive oxygen species.