Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
Nephrology and Urology Research Institute of Wuhan University, Wuhan, Hubei, China.
Cell Prolif. 2022 Jun;55(6):e13229. doi: 10.1111/cpr.13229. Epub 2022 May 14.
Exposure of podocytes to angiotensin II (Ang II) enhances the abundance of the cell surface glycoprotein, low-density lipoprotein receptor (LDLR) and promotes significant changes in the cellular cholesterol content. Recent investigation provides evidence that the small GTPase Rab11 is involved in the regulation of LDLR, but the exact mechanisms remain unknown. In this study, the role of Rab11 in post-transcriptional regulation of LDLR was evaluated to investigate potential mechanisms of podocyte cholesterol dysregulation in chronic kidney disease.
Cholesterol content, LDLR and Rab11 expression were assessed in podocytes from Ang II-infused mice. In vitro, the intracellular localization of LDLR was detected under different conditions. Rab11 expression was modulated and we then explored the effect of anti-lipid cytotoxicity by detecting LDLR expression and trafficking, cholesterol content and apoptosis in podocytes.
Cholesterol accumulation, upregulated expression of LDLR and Rab11 were discovered in podocytes from Ang II-infused mice. Ang II enhanced the co-precipitation of LDLR with Rab11 and accelerated the endocytic recycling of LDLR to the plasma membrane. Additionally, silencing Rab11 promoted lysosomal degradation of LDLR and alleviated Ang II-induced cholesterol accumulation and apoptosis in podocytes. Conversely, overexpression of Rab11 or inhibition of lysosomal degradation up-regulated the abundance of LDLR and aggravated podocyte cholesterol deposition.
Rab11 triggers the endocytic trafficking and recycling of LDLR; overactivation of this pathway contributes to Ang II-induced podocyte cholesterol accumulation and injury.
血管紧张素 II（Ang II）使足细胞暴露，增加细胞表面糖蛋白低密度脂蛋白受体（LDLR）的含量，并使细胞内胆固醇含量发生显著变化。最近的研究表明，小 GTPase Rab11 参与 LDLR 的调节，但确切的机制尚不清楚。在这项研究中，评估了 Rab11 在 LDLR 转录后调节中的作用，以研究慢性肾脏病中足细胞胆固醇失调的潜在机制。
检测 Ang II 灌注小鼠足细胞中的胆固醇含量、LDLR 和 Rab11 的表达。在体外，在不同条件下检测 LDLR 的细胞内定位。调节 Rab11 的表达，然后通过检测 LDLR 的表达和转运、胆固醇含量和足细胞凋亡来探索抗脂质细胞毒性的作用。
在 Ang II 灌注的小鼠足细胞中发现胆固醇积累、LDLR 和 Rab11 的表达上调。Ang II 增强了 LDLR 与 Rab11 的共沉淀，并加速了 LDLR 到质膜的内吞循环。此外，沉默 Rab11 促进了 LDLR 的溶酶体降解，并减轻了 Ang II 诱导的足细胞胆固醇积累和凋亡。相反，Rab11 的过表达或溶酶体降解的抑制增加了 LDLR 的丰度，并加重了足细胞胆固醇沉积。
Rab11 触发 LDLR 的内吞转运和循环；该途径的过度激活导致 Ang II 诱导的足细胞胆固醇积累和损伤。
