Renal injury leads to chronic kidney disease for which women are not only more likely to be diagnosed with than men but have poorer outcomes as well. We have previously shown that expression of Sprr2f, a member of the Small Proline Rich Region (Sprr) gene family, is increased several hundred-fold 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 to wild type (Sprr2f-WT) animals, evidenced by higher hydroxyproline levels and denser collagen staining, indicating a protective role of Sprr2f during renal injury. Gene expression profiling by RNA-seq identified 162 genes whose expression levels were significantly different between day 0 and day 5 after UUO in Sprr2f-KO mice. Out of the 162 genes, 121 were upregulated after UUO and enriched with those involved in oxidation-reduction, a phenomenon not observed in wild type 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 level and higher tissue reactive oxygen species (ROS) in Sprr2f-KO compared to Sprr2f-WT female mice. Moreover, cultured renal epithelial cells from Sprr2f-KO female mice showed lower viability after oxidative damage induced by menadione compared to Sprr2f-WT cells that could be rescued by supplementation with reduced glutathione, suggesting that Sprr2f induction after renal damage acts as a defense against ROS.

中文翻译：

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Sprr2f 通过降低雌性小鼠的活性氧水平来防止肾损伤

肾损伤导致慢性肾病，女性不仅比男性更有可能被诊断出患有这种疾病，而且结果也更差。我们之前已经表明，在使用单侧输尿管梗阻 (UUO) 小鼠模型肾损伤后，Sprr2f（小脯氨酸富集区 (Sprr) 基因家族的成员）的表达增加了数百倍。为了更好地了解 Sprr2f 在肾损伤中的作用，我们使用 CRISPR-Cas9 技术生成了 Sprr2f 敲除 (Sprr2f-KO) 小鼠模型。与野生型 (Sprr2f-WT) 动物相比，Sprr2f-KO 雌性小鼠在 UUO 后表现出更大的肾损伤，这由更高的羟脯氨酸水平和更密集的胶原染色证明，表明 Sprr2f 在肾损伤期间具有保护作用。通过 RNA-seq 进行的基因表达分析鉴定了 162 个基因，其表达水平在 Sprr2f-KO 小鼠中 UUO 后第 0 天和第 5 天之间存在显着差异。在 162 个基因中，有 121 个在 UUO 后上调，并富含参与氧化还原的基因，这种现象在野生型动物中未观察到，表明 Sprr2f 通过防御氧化损伤在 UUO 中发挥保护作用。一致地，与 Sprr2f-WT 雌性小鼠相比，双侧缺血再灌注损伤导致 Sprr2f-KO 中更高的血清尿素氮水平和更高的组织活性氧 (ROS)。此外，与可以通过补充还原型谷胱甘肽来挽救的 Sprr2f-WT 细胞相比，来自 Sprr2f-KO 雌性小鼠的培养的肾上皮细胞在甲萘醌诱导的氧化损伤后显示出较低的活力，