Ji Hong, Menini Stefano, Zheng Wei, Pesce Carlo, Wu Xie, Sandberg Kathryn
Center for the Study of Sex Differences in Health, Aging and Disease, Georgetown University, Washington, DC, USA.
Exp Physiol. 2008 May;93(5):648-57. doi: 10.1113/expphysiol.2007.041392. Epub 2008 Feb 22.
17beta-Oestradiol (E2)-mediated inhibition of angiotensin-converting enzyme (ACE) protects the E2-replete kidney from the progression of hypertensive renal disease. Angiotensin-converting enzyme 2 (ACE2), a homologue of ACE, counters the actions of ACE by catalysing the conversion of angiotensin II (Ang II) to angiotensin(1-7) [Ang(1-7)]. We investigated E2 regulation of ACE2 in the renal wrap (RW) model of hypertension in rats. After 6 weeks on a high-sodium diet (4% NaCl), the activity of ACE2 was reduced in the renal cortex by 31%, which was mirrored by similar decreases in ACE2 protein (30%) and mRNA expression (36%) in the ovariectomized RW rat (RW-OVX); E2 replacement prevented these effects. The RW-OVX rats exhibited greater renal injury, including 1.7-fold more tubulointerstitial fibrosis and 1.6-fold more glomerulosclerosis than E2-replete females (RW-Intact and RW-OVX+E2). Angiotensin(1-7) infusion prevented these exacerbating effects of ovariectomy on renal pathology; no differences in indicators of renal injury were observed between RW-OVX-Ang(1-7) and RW-Intact rats. These renal protective effects of Ang(1-7) infusion were not attributable to increased ACE2 activity or to changes in heart rate or body weight, since these parameters were unchanged by Ang(1-7) infusion. Furthermore, Ang(1-7) infusion did not attenuate renal injury by reducing mean arterial pressure (MAP), since infusion of the peptide did not lower MAP but rather caused a slight increase during a 6 week chronic treatment for Ang(1-7). These results suggest that E2-mediated upregulation of renal ACE2 and the consequent increased Ang(1-7) production contribute to E2-mediated protection from hypertensive renal disease. These findings have implications for E2-deficient women with hypertensive renal disease and suggest that therapeutics targeted towards increasing ACE2 activity and Ang(1-7) levels will be renal protective.
17β-雌二醇（E2）介导的血管紧张素转换酶（ACE）抑制作用可保护雌激素充足的肾脏免受高血压性肾病进展的影响。血管紧张素转换酶2（ACE2）是ACE的同源物，通过催化血管紧张素II（Ang II）转化为血管紧张素（1-7）[Ang（1-7）]来对抗ACE的作用。我们在大鼠高血压肾包膜（RW）模型中研究了E2对ACE2的调节作用。在高钠饮食（4% NaCl）喂养6周后，去卵巢RW大鼠（RW-OVX）肾皮质中ACE2的活性降低了31%，ACE2蛋白（30%）和mRNA表达（36%）也有类似程度的下降；补充E2可防止这些影响。与雌激素充足的雌性大鼠（RW-Intact和RW-OVX+E2）相比，RW-OVX大鼠表现出更严重的肾损伤，包括肾小管间质纤维化增加1.7倍和肾小球硬化增加1.6倍。输注血管紧张素（1-7）可防止去卵巢对肾脏病理的这些加重作用；在RW-OVX-Ang（1-7）大鼠和RW-Intact大鼠之间未观察到肾损伤指标的差异。输注血管紧张素（1-7）的这些肾脏保护作用并非归因于ACE2活性增加或心率或体重的变化，因为这些参数在输注血管紧张素（1-7）后未发生改变。此外，输注血管紧张素（1-7）并未通过降低平均动脉压（MAP）来减轻肾损伤，因为在6周的血管紧张素（1-7）慢性治疗期间，输注该肽并未降低MAP，反而导致轻微升高。这些结果表明，E2介导的肾脏ACE2上调以及随之而来的血管紧张素（1-7）生成增加有助于E2介导的对高血压性肾病的保护作用。这些发现对患有高血压性肾病的雌激素缺乏女性具有启示意义，并表明旨在增加ACE2活性和血管紧张素（1-7）水平的治疗方法将具有肾脏保护作用。
