Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Suita City, Japan.
Hypertens Res. 2010 Apr;33(4):298-307. doi: 10.1038/hr.2009.231. Epub 2010 Feb 26.
As angiotensin-converting enzyme-2 (ACE2) was identified as a negative regulator of the renin-angiotensin system, there have been many reports concerning its role in several tissues, including the kidney. However, the role of ACE2 during the development of diabetic nephropathy remains undetermined, as previous reports did not necessarily support a protective role against renal injury. Thus, we performed detailed observations of kidneys in ACE2-knockout (ACE2-KO) mice at early (4 weeks) and advanced (18 weeks) stages of diabetes. ACE2-KO and wild-type C57BL/6 mice were rendered diabetic by intraperitoneal injection of streptozotocin. Diabetic ACE2-KO mice showed earlier onset and more severe progression of albuminuria than those did wild-type mice. The elevation of serum creatinine and urea nitrogen levels at 18 weeks of diabetes was more prominent in ACE2-KO mice. Periodic acid-Schiff-stained cross-section of diabetic ACE2-KO mice showed a more severe time-dependent increase in glomerular/tubulointerstitial damage than did that of wild-type mice, confirmed by the immunostaining of alpha-smooth muscle actin, collagen IV and F4-80 antigen. Glomeruli of diabetic ACE2-KO mice showed earlier and more severe decrease in the expression of nephrin, whose degradation is involved in the onset of albuminuria, and more potent increase of vascular endothelial growth factor expression. In addition, treatment with AT1 receptor blocker olmesartan significantly, but not totally, ameliorated the functional and morphological deterioration of diabetic nephropathy in ACE2-KO mice. These results suggest that ACE2 might continuously protect from both glomerular and tubulointerstitial injury during the development of diabetic nephropathy. The renal-protective effect of ACE2 might involve more than just suppressing angiotensin II-mediated AT1 receptor signaling.
血管紧张素转换酶 2（ACE2）被鉴定为肾素-血管紧张素系统的负调节剂，已有许多关于其在包括肾脏在内的几种组织中作用的报道。然而，ACE2 在糖尿病肾病发展过程中的作用仍不确定，因为之前的报道并不一定支持其对肾损伤的保护作用。因此，我们在糖尿病早期（4 周）和晚期（18 周）对 ACE2 敲除（ACE2-KO）小鼠的肾脏进行了详细观察。通过腹腔注射链脲佐菌素使 ACE2-KO 和野生型 C57BL/6 小鼠发生糖尿病。糖尿病 ACE2-KO 小鼠比野生型小鼠更早出现更严重的蛋白尿。糖尿病 18 周时，血清肌酐和尿素氮水平升高更为明显。ACE2-KO 小鼠糖尿病 PAS 染色的横切片显示肾小球/肾小管间质损伤呈更严重的时间依赖性增加，野生型小鼠的情况也是如此，α-平滑肌肌动蛋白、胶原 IV 和 F4-80 抗原的免疫染色证实了这一点。糖尿病 ACE2-KO 小鼠的肾小球更早且更严重地降低了足细胞裂孔隔膜蛋白 Nephrin 的表达，Nephrin 的降解参与了蛋白尿的发生，血管内皮生长因子的表达也更强烈增加。此外，AT1 受体阻滞剂奥美沙坦治疗可显著但不完全改善 ACE2-KO 小鼠糖尿病肾病的功能和形态恶化。这些结果表明，ACE2 可能在糖尿病肾病的发展过程中持续保护肾小球和肾小管间质免受损伤。ACE2 的肾脏保护作用可能不仅仅涉及抑制血管紧张素 II 介导的 AT1 受体信号。
