From the Division of Molecular Genetics, Shigei Medical Research Institute, and
From the Division of Molecular Genetics, Shigei Medical Research Institute, and.
J Biol Chem. 2014 Nov 7;289(45):31526-33. doi: 10.1074/jbc.M114.584565. Epub 2014 Sep 24.
Renal fibrosis is responsible for progressive renal diseases that cause chronic renal failure. Sfrp1 (secreted Frizzled-related protein 1) is highly expressed in kidney, although little is known about connection between the protein and renal diseases. Here, we focused on Sfrp1 to investigate its roles in renal fibrosis using a mouse model of unilateral ureteral obstruction (UUO). In wild-type mice, the expression of Sfrp1 protein was markedly increased after UUO. The kidneys from Sfrp1 knock-out mice showed significant increase in expression of myofibrobast markers, α-smooth muscle actin (αSMA). Sfrp1 deficiency also increased protein levels of the fibroblast genes, vimentin, and decreased those of the epithelial genes, E-cadherin, indicated that enhanced epithelial-to-mesenchymal transition. There was no difference in the levels of canonical Wnt signaling; rather, the levels of phosphorylated c-Jun and JNK were more increased in the Sfrp1(-/-) obstructed kidney. Moreover, the apoptotic cell population was significantly elevated in the obstructed kidneys from Sfrp1(-/-) mice following UUO but was slightly increased in those from wild-type mice. These results indicate that Sfrp1 is required for inhibition of renal damage through the non-canonical Wnt/PCP pathway.
肾纤维化是导致慢性肾衰竭的进行性肾脏疾病的罪魁祸首。Sfrp1（分泌型卷曲相关蛋白 1）在肾脏中高度表达，但关于该蛋白与肾脏疾病之间的联系知之甚少。在这里，我们使用单侧输尿管梗阻（UUO）的小鼠模型专注于 Sfrp1，以研究其在肾纤维化中的作用。在野生型小鼠中，Sfrp1 蛋白的表达在 UUO 后明显增加。Sfrp1 敲除小鼠的肾脏中肌成纤维细胞标志物α-平滑肌肌动蛋白（αSMA）的表达显著增加。Sfrp1 缺失还增加了成纤维细胞基因 vimentin 的蛋白水平，降低了上皮基因 E-钙粘蛋白的水平，表明增强了上皮-间充质转化。经典 Wnt 信号通路的水平没有差异；相反，Sfrp1（-/-）梗阻肾脏中磷酸化 c-Jun 和 JNK 的水平增加更多。此外，UUO 后 Sfrp1（-/-）小鼠梗阻肾脏中的凋亡细胞群体明显升高，而野生型小鼠中的凋亡细胞群体略有升高。这些结果表明，Sfrp1 通过非经典 Wnt/PCP 通路抑制肾脏损伤是必需的。
