Oestreicher E M, Guo C, Seely E W, Kikuchi T, Martinez-Vasquez D, Jonasson L, Yao T, Burr D, Mayoral S, Roubsanthisuk W, Ricchiuti V, Adler G K
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Kidney Int. 2006 Nov;70(10):1759-68. doi: 10.1038/sj.ki.5001897. Epub 2006 Oct 4.
Prospective, placebo-controlled clinical trials suggest that estrogen may have adverse effects on the vascular system in women. The goal of this study was to determine if 17beta-estradiol (E2) would have adverse effects on the renovasculature in a rat model of renal injury characterized by low nitric oxide (NO) and high angiotensin II (AngII). We studied female Wistar rats that were sham-operated (sham), ovariectomized (OVX), or ovariectomized and replaced with E2 (OVX/E2). All rats were maintained on a high salt diet and renovascular injury was caused by treating rats with an inhibitor of NO synthase, N(omega)-nitro-L-arginine-methyl-ester (L-NAME), for 14 days, plus AngII on days 11 through 14. L-NAME/AngII treatment, as compared to placebo, caused proteinuria, glomerular injury, and fibrinoid necrosis of renal arterioles in sham-operated rats. Ovariectomy reduced L-NAME/AngII-induced renal damage, whereas E2 treatment increased L-NAME/AngII-induced damage in OVX rats. In rats treated with L-NAME/AngII, levels of AngII type 1 receptor (AT(1)R) protein were higher in the renal cortex of sham and OVX/E2 rats than in OVX rats. AT(1)R protein correlated with renal injury. E2 treatment also increased expression of AT(1)R mRNA. Thus, under conditions of low NO and high AngII, E2 exacerbated renal injury. E2-mediated increases in renal cortical AT(1)R expression may represent a novel mechanism for the adverse renovascular effects of estrogen.
前瞻性、安慰剂对照临床试验表明，雌激素可能对女性血管系统产生不良影响。本研究的目的是确定17β-雌二醇（E2）在以低一氧化氮（NO）和高血管紧张素II（AngII）为特征的肾损伤大鼠模型中是否会对肾血管系统产生不良影响。我们研究了假手术（假手术组）、卵巢切除（OVX组）或卵巢切除并用E2替代（OVX/E2组）的雌性Wistar大鼠。所有大鼠均维持高盐饮食，通过用NO合酶抑制剂N（ω）-硝基-L-精氨酸甲酯（L-NAME）处理大鼠14天，并在第11至14天给予AngII来诱导肾血管损伤。与安慰剂相比，L-NAME/AngII处理导致假手术组大鼠出现蛋白尿、肾小球损伤和肾小动脉纤维蛋白样坏死。卵巢切除减少了L-NAME/AngII诱导的肾损伤，而E2处理增加了OVX大鼠中L-NAME/AngII诱导的损伤。在用L-NAME/AngII处理的大鼠中，假手术组和OVX/E2组大鼠肾皮质中血管紧张素II 1型受体（AT（1）R）蛋白水平高于OVX组大鼠。AT（1）R蛋白与肾损伤相关。E2处理还增加了AT（1）R mRNA的表达。因此，在低NO和高AngII条件下，E2加剧了肾损伤。E2介导的肾皮质AT（1）R表达增加可能代表雌激素对肾血管产生不良影响的一种新机制。
