Department of Nephrology, Shengjing Hospital of China Medical University, Shenyang, 110004, People's Republic of China.
Department of Nephrology, Shengjing Hospital of China Medical University, Shenyang, 110004, People's Republic of China.
Exp Cell Res. 2021 Aug 15;405(2):112713. doi: 10.1016/j.yexcr.2021.112713. Epub 2021 Jun 25.
Obesity, a global epidemic, is one of the critical causes of chronic kidney disease (CKD). R-spondin1 (RSPO1) possessing the potential to activate Wnt/β-catenin pathway was reported to be elevated in circulation of obesity objects. However, the function of RSPO1 and the latent mechanism in obesity-related CKD are still left to be revealed. In the present study, renal RSPO1 expression was increased in mice fed on high-fat diet (HFD) for 12 weeks. Lentivirus-mediated RSPO1 knockdown partly recovered obesity-related metabolic symptoms, while distinctly remitted kidney dysfunction and renal fibrosis in obesity mice. In vitro, recombinant RSPO1 was found to elevate leucine-rich repeat-containing G protein coupled receptor 4 (LGR4) expression, promote Wnt/β-catenin signaling pathway activation, facilitate epithelial-mesenchymal transition (EMT) and increase collagen deposition in HK2 renal tubular cells. Such pro-fibrotic effect of RSPO1 was diminished by LGR4 siRNA in HK2 cells. In summary, we demonstrate that RSPO1/LGR4 axis is involved in obesity-related renal fibrosis at least through activating Wnt/β-catenin signaling pathway, providing a potential therapeutic target for this disease.
肥胖症是全球性的流行病，是慢性肾脏病（CKD）的重要原因之一。RSPO1（R-spondin1）具有激活 Wnt/β-连环蛋白通路的潜力，据报道在肥胖症患者的循环中升高。然而，RSPO1 的功能及其在肥胖相关 CKD 中的潜在机制仍有待揭示。在本研究中，高脂肪饮食喂养 12 周的小鼠肾脏 RSPO1 表达增加。慢病毒介导的 RSPO1 敲低部分恢复了肥胖相关的代谢症状，同时明显减轻了肥胖小鼠的肾功能障碍和肾纤维化。在体外，重组 RSPO1 被发现可上调富含亮氨酸重复的 G 蛋白偶联受体 4（LGR4）的表达，促进 Wnt/β-连环蛋白信号通路的激活，促进上皮-间充质转化（EMT）并增加 HK2 肾小管细胞的胶原沉积。在 HK2 细胞中，LGR4 siRNA 减弱了 RSPO1 的这种促纤维化作用。总之，我们证明了 RSPO1/LGR4 轴至少通过激活 Wnt/β-连环蛋白信号通路参与肥胖相关的肾纤维化，为该疾病提供了一个潜在的治疗靶点。
