From the State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, and Shanghai Institute of Hypertension, China (J.-r.L., Z.-b.Z., W.-l.S., X.-d.L., T.W., C.-c.R., D.-l.Z., P.-j.G.).
Laboratory of Vascular Biology and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China (Y.-j.Z., X.-h.C., P.-j.G.).
Hypertension. 2018 Aug;72(2):350-360. doi: 10.1161/HYPERTENSIONAHA.118.10482. Epub 2018 Jun 18.
Endothelial-to-mesenchymal transition (EndoMT) has recently emerged as a potentially important contributor in promoting fibrosis in chronic kidney disease. However, little is known about the role and molecular basis of its involvement in hypertensive renal injury. Here, we aim to determine the role of SIRT (sirtuin) 3 on EndoMT in hypertensive renal injury and to explore its underlying mechanisms. We found that SIRT3 expression was significantly reduced in Ang II (angiotensin II)-induced hypertensive model, accompanied with induction of EndoMT and increased reactive oxygen species and renal fibrosis. In SIRT3 (SIRT3 knockout) mice subjected to Ang II infusion, renal dysfunction was aggravated with an increased EndoMT and reactive oxygen species level, whereas in SIRT3-Tg (SIRT3 endothelial cell-specific transgenic) mice, the Ang II-induced renal fibrosis and EndoMT and oxidative stress were ameliorated. With primary mouse glomerular endothelial cells, we confirmed that Ang II treatment initiated EndoMT and decreased catalase expression, which were suppressed by SIRT3 overexpression. Using immunoprecipitation, luciferase, and chromatin immunoprecipitation assay, we demonstrated that SIRT3-mediated deacetylation and nuclear localization of Foxo3a (forkhead box O3a) resulted in activated Foxo3a-dependent catalase expression. Moreover, Foxo3a knockdown abolished SIRT3-mediated suppression of EndoMT. In conclusion, these results established the SIRT3-Foxo3a-catalase pathway as a critical factor in the maintenance of endothelial homeostasis and point to an important role of EndoMT in the vascular pathology of renal fibrosis, which may provide a new therapeutic target to impede the progression of hypertensive renal injury.
内皮-间充质转化（EndoMT）最近被认为是促进慢性肾脏病纤维化的一个潜在重要因素。然而，其在高血压肾损伤中的作用及其分子基础知之甚少。在这里，我们旨在确定 SIRT（沉默信息调节因子 2 相关酶 3）3 在高血压肾损伤中的 EndoMT 中的作用，并探讨其潜在机制。我们发现，SIRT3 表达在 Ang II（血管紧张素 II）诱导的高血压模型中显著降低，伴随着 EndoMT 的诱导以及活性氧和肾纤维化的增加。在接受 Ang II 输注的 SIRT3（SIRT3 敲除）小鼠中，肾功能障碍加重，EndoMT 和活性氧水平增加，而在 SIRT3-Tg（SIRT3 内皮细胞特异性转基因）小鼠中，Ang II 诱导的肾纤维化和 EndoMT 以及氧化应激得到改善。使用原代小鼠肾小球内皮细胞，我们证实 Ang II 处理引发了 EndoMT，并降低了过氧化氢酶的表达，而过表达 SIRT3 则抑制了这一过程。通过免疫沉淀、荧光素酶和染色质免疫沉淀实验，我们证明了 SIRT3 介导的 Foxo3a（叉头框 O3a）去乙酰化和核定位导致了 Foxo3a 依赖性过氧化氢酶表达的激活。此外，Foxo3a 的敲低消除了 SIRT3 介导的对 EndoMT 的抑制。总之，这些结果确立了 SIRT3-Foxo3a-过氧化氢酶途径作为维持内皮细胞稳态的关键因素，并指出了 EndoMT 在肾纤维化血管病变中的重要作用，这可能为阻止高血压肾损伤的进展提供了一个新的治疗靶点。
