Supplemental Digital Content is available in the text. Arhgef11 is a Rho-guanine nucleotide exchange factor that was previously implicated in kidney injury in the Dahl salt-sensitive (SS) rat, a model of hypertension-related chronic kidney disease. Reduced Arhgef11 expression in an SS-Arhgef11SHR-minimal congenic strain (spontaneously hypertensive rat allele substituted for S allele) significantly decreased proteinuria, fibrosis, and improved renal hemodynamics, without impacting blood pressure compared with the control SS (SS-wild type). Here, SS-Arhgef11−/− and SS-wild type rats were placed on either low or elevated salt (0.3% or 2% NaCl) from 4 to 12 weeks of age. On low salt, starting at week 6 and through week 12, SS-Arhgef11−/− animals demonstrated a 3-fold decrease in proteinuria compared with SS-wild type. On high salt, beginning at week 6, SS-Arhgef11−/− animals demonstrated >2-fold lower proteinuria from weeks 8 to 12 and 30 mm Hg lower BP compared with SS-wild type. To better understand the molecular mechanisms of the renal protection from loss of Arhgef11, both RNA sequencing and discovery proteomics were performed on kidneys from week 4 (before onset of renal injury/proteinuria between groups) and at week 12 (low salt). The omics data sets revealed loss of Arhgef11 (SS-Arhgef11−/−) initiates early transcriptome/protein changes in the cytoskeleton starting as early as week 4 that impact a number of cellular functions, including actin cytoskeletal regulation, mitochondrial metabolism, and solute carrier transporters. In summary, in vivo phenotyping coupled with a multi-omics approach provides strong evidence that increased Arhgef11 expression in the Dahl SS rat leads to actin cytoskeleton-mediated changes in cell morphology and cell function that promote kidney injury, hypertension, and decline in kidney function.

中文翻译：

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达尔盐敏感大鼠中 Arhgef11 的缺失可防止高血压引起的肾损伤

补充数字内容在文本中可用。Arhgef11 是一种 Rho-鸟嘌呤核苷酸交换因子，以前与 Dahl 盐敏感 (SS) 大鼠（一种高血压相关慢性肾病模型）的肾损伤有关。与对照 SS（SS 野生型）相比，SS-Arhgef11SHR 最小同类菌株（自发性高血压大鼠等位基因取代 S 等位基因）中 Arhgef11 表达降低显着降低蛋白尿、纤维化和改善肾血流动力学，而不会影响血压。在这里，SS-Arhgef11-/- 和 SS-野生型大鼠在 4 至 12 周龄期间被置于低盐或高盐（0.3% 或 2% NaCl）中。在低盐条件下，从第 6 周开始到第 12 周，与 SS 野生型相比，SS-Arhgef11-/- 动物的蛋白尿减少了 3 倍。高盐，从第 6 周开始，与 SS 野生型相比，SS-Arhgef11-/- 动物从第 8 周到第 12 周的蛋白尿降低了 2 倍以上，血压降低了 30 mmHg。为了更好地了解肾脏保护免受 Arhgef11 丢失的分子机制，在第 4 周（组间肾损伤/蛋白尿发生之前）和第 12 周（低盐）对肾脏进行了 RNA 测序和发现蛋白质组学。组学数据集显示 Arhgef11 (SS-Arhgef11−/−) 的缺失早在第 4 周就开始了细胞骨架中的早期转录组/蛋白质变化，这会影响许多细胞功能，包括肌动蛋白细胞骨架调节、线粒体代谢和溶质载体运输者。总之，