Department of Endocrinology & Metabolism, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510630, China.
Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
Signal Transduct Target Ther. 2020 Apr 29;5(1):45. doi: 10.1038/s41392-020-0142-x.
Previous studies by us and others demonstrated that activation of Wnt/β-catenin signaling plays a pathogenic role in chronic kidney diseases (CKD). Wnt co-receptor LRP5 variants are reported to associate with autosomal dominant polycystic kidney disease; but their exact roles in this disease and renal fibrosis have not been explored. Here, we observed the upregulation of LRP5 in the renal tubules of both type 1 and type 2 diabetic models and of an obstructive nephropathy model. In the obstructed kidneys, Lrp5 knockout significantly ameliorated tubulointerstitial fibrosis and tubular injury without changing Wnt/β-catenin signaling. Instead, decreased levels of TGF-β1 and TGF-β receptors (TβRs) were detected in Lrp5 knockout kidneys, followed by attenuated activation and nuclear translocation of Smad2/3 in the renal tubules, suggesting a regulatory effect of LRP5 on TGF-β/Smad signaling. In consistent with this hypothesis, LRP5 overexpression resulted in enhanced TGF-β/Smad signaling activation in renal tubule epithelial cells. Furthermore, LRP5 was co-immunoprecipitated with TβRI and TβRII, and its extracellular domain was essential for interacting with TβRs and for its pro-fibrotic activity. In addition to stabilizing TβRs, LRP5 increased the basal membrane presentation and TGF-β1-induced internalization of these receptors. Notably, TGF-β1 also induced LRP5 internalization. These findings indicate that LRP5 promotes tubulointerstitial fibrosis, at least partially, via direct modulation of TGF-β/Smad signaling, a novel, Wnt-independent function.
先前我们和其他研究人员的研究表明，Wnt/β-连环蛋白信号通路的激活在慢性肾脏病（CKD）中发挥着致病作用。报道称 Wnt 共受体 LRP5 变体与常染色体显性多囊肾病有关；但其在该疾病和肾纤维化中的确切作用尚未得到探索。在这里，我们观察到 1 型和 2 型糖尿病模型以及梗阻性肾病模型的肾小管中 LRP5 的上调。在梗阻性肾脏中，Lrp5 敲除显著改善了肾小管间质纤维化和肾小管损伤，而不会改变 Wnt/β-连环蛋白信号通路。相反，在 Lrp5 敲除肾脏中检测到 TGF-β1 和 TGF-β 受体（TβRs）水平降低，随后肾小管中 Smad2/3 的激活和核转位减弱，表明 LRP5 对 TGF-β/Smad 信号具有调节作用。与该假说一致，LRP5 过表达导致肾小管上皮细胞中 TGF-β/Smad 信号激活增强。此外，LRP5 与 TβRI 和 TβRII 共免疫沉淀，其细胞外结构域对于与 TβRs 相互作用及其促纤维化活性是必需的。除了稳定 TβRs 外，LRP5 还增加了这些受体的基底膜呈现和 TGF-β1 诱导的内化。值得注意的是，TGF-β1 也诱导了 LRP5 的内化。这些发现表明，LRP5 通过直接调节 TGF-β/Smad 信号通路（一种新的、不依赖 Wnt 的功能）促进肾小管间质纤维化，至少部分是这样。
