From the Division of Nephrology, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China (Z.L., J.L.); Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Shatin, Hong Kong SAR, China (Z.L., X.-R.H., H.-Y.C., E.F., H.-Y.L.); and Shenzhen Research Institute, Chinese University of Hong Kong, Shatin, Hong Kong SAR, China (Z.L., X.-R.H., H.-Y.C., E.F., H.-Y.L.).
Hypertension. 2017 Oct;70(4):822-830. doi: 10.1161/HYPERTENSIONAHA.117.09600. Epub 2017 Aug 14.
Angiotensin-converting enzyme-2 (ACE2) is downregulated in hypertensive nephropathy. The present study investigated the mechanisms whereby loss of ACE2 promoted angiotensin II-induced hypertensive nephropathy in ACE2 gene knockout mice. We found that compared with wild-type animals, mice lacking ACE2 developed much more severe hypertensive nephropathy in response to chronic angiotensin II infusion, including higher levels of blood pressure, urinary protein excretion, serum creatinine, and progressive renal fibrosis and inflammation. Mechanistic studies revealed that worsening kidney injury in ACE2 knockout mice was associated with an increase in Smurf2 (Smad-specific E3 ubiquitin protein ligase 2), a decrease in renal Smad7, and marked activation of TGF-β (transforming growth factor β)/Smad3 and NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) signaling, suggesting that Smurf2-dependent Smad7 ubiquitin degradation may be a key mechanism whereby loss of ACE2 promotes angiotensin II-induced TGF-β/Smad3 and NF-κB-mediated hypertensive nephropathy. This was validated by restoring Smad7 locally in the kidneys of ACE2 knockout mice to block angiotensin II-induced TGF-β/Smad3-mediated renal fibrosis and NF-κB-driven renal inflammation. Moreover, we found that angiotensin II could induce microRNA-21 in the mouse kidney and in cultured mesangial cells via a Smad3-dependent mechanism, which was enhanced by deleting ACE2 but inhibited by overexpressing renal Smad7. In conclusion, loss of ACE2 promotes angiotensin II-induced renal injury by targeting Smad7 for degradation via a Smurf2-dependent mechanism. Overexpression of renal Smad7 protects against hypertensive nephropathy by inactivating angiotensin II-induced TGF-β/Smad3 and NF-κB pathways and by targeting the Smad3-dependent microRNA-21 axis.
血管紧张素转换酶 2（ACE2）在高血压肾病中下调。本研究探讨了 ACE2 缺失促进 ACE2 基因敲除小鼠血管紧张素 II 诱导的高血压肾病的机制。我们发现，与野生型动物相比，缺乏 ACE2 的小鼠在慢性血管紧张素 II 输注时会发生更严重的高血压肾病，包括血压升高、尿蛋白排泄、血清肌酐以及进行性肾纤维化和炎症。机制研究表明，ACE2 敲除小鼠肾脏损伤加重与 Smurf2（Smad 特异性 E3 泛素蛋白连接酶 2）增加、肾脏 Smad7 减少以及 TGF-β（转化生长因子-β）/Smad3 和 NF-κB（核因子 κ-轻链增强子的激活 B 细胞）信号转导的显著激活有关，表明 Smurf2 依赖性 Smad7 泛素降解可能是 ACE2 缺失促进血管紧张素 II 诱导的 TGF-β/Smad3 和 NF-κB 介导的高血压肾病的关键机制。通过在 ACE2 敲除小鼠的肾脏中局部恢复 Smad7 来阻断血管紧张素 II 诱导的 TGF-β/Smad3 介导的肾纤维化和 NF-κB 驱动的肾炎症，验证了这一点。此外，我们发现血管紧张素 II 可以通过 Smad3 依赖性机制在小鼠肾脏和培养的系膜细胞中诱导 microRNA-21，这种机制在 ACE2 缺失时增强，而在过表达肾脏 Smad7 时受到抑制。总之，ACE2 的缺失通过 Smurf2 依赖性机制靶向 Smad7 降解，促进血管紧张素 II 诱导的肾脏损伤。肾脏 Smad7 的过表达通过使血管紧张素 II 诱导的 TGF-β/Smad3 和 NF-κB 途径失活，并靶向 Smad3 依赖性 microRNA-21 轴，来防止高血压肾病。
