Gross Marie-Luise, Adamczak Marcin, Rabe Thomas, Harbi Nevin Ali, Krtil Jan, Koch Andreas, Hamar Peter, Amann Kerstin, Ritz Eberhard
Departments of Pathology and Internal Medicine, University of Heidelberg, Heidelberg, Germany.
J Am Soc Nephrol. 2004 Feb;15(2):348-58. doi: 10.1097/01.asn.0000105993.63023.d8.
Renal diseases tend to be less severe among premenopausal female patients, compared with male patients. Experimental data on the effects of estrogens on renal damage are controversial, and potential underlying mechanisms have not been fully clarified. Three-month-old, female, uninephrectomized (UNX), sham-operated or ovariectomized (OVX) SHRsp rats were left untreated or received either 17beta-estradiol 3-benzoate (25 micro g/d) or estriol (0.02 mg/d) daily. After 3 mo, indices of renal damage (glomerulosclerosis index and tubulointerstitial damage index) and glomerular geometric parameters were investigated. The expression of desmin, TGF-beta, endothelin-1, collagen IV, endothelial nitric oxide synthase, and estrogen receptors alpha and beta in the glomeruli and tubulointerstitium was immunohistochemically evaluated. Estradiol and estriol did not significantly affect kidney weights or BP. Estradiol and estriol caused significant reductions in albuminuria (vehicle-treated UNX/OVX animals, 25.4 +/- 8.52 mg/24 h; estradiol-treated UNX/OVX animals, 15.37 +/- 6.12 mg/24 h; estriol-treated UNX/OVX animals, 6.54 +/- 2.24 mg/24 h). The glomerulosclerosis index was significantly lower in estriol- and estradiol-treated animals (estradiol-treated UNX/OVX animals, 0.69 +/- 0.16; estriol-treated UNX/OVX animals, 0.21 +/- 0.12; P < 0.05), compared with vehicle-treated animals (1.46 +/- 0.09); the tubulointerstitial damage index exhibited a similar pattern. The mean glomerular volume was significantly less in estrogen-treated animals. UNX/OVX animals demonstrated significantly greater expression of TGF-beta and endothelin-1 in immunohistochemical, in situ hybridization, and reverse transcription-PCR assays. This increase was abrogated by estriol but not estradiol. Similarly, significantly higher glomerular and tubulointerstitial expression of proliferating cell nuclear antigen and collagen IV was observed in UNX/OVX animals, and expression was decreased by estriol but not estradiol. It was concluded that, in the UNX model of spontaneous renal damage, glomerular lesions and glomerular hypertrophy were reduced by estriol but less consistently by estradiol. In parallel, loss of podocytes, evidence of podocyte injury (i.e., desmin expression), and expression of mediator systems of glomerular damage were decreased, pointing to a major renoprotective action of estriol.
与男性患者相比，绝经前女性患者的肾脏疾病往往病情较轻。关于雌激素对肾脏损伤影响的实验数据存在争议，其潜在的潜在机制尚未完全阐明。对3个月大的雌性未切除单侧肾脏（UNX）、假手术或去卵巢（OVX）的自发性高血压大鼠（SHRsp）不进行治疗，或每天给予17β-雌二醇3-苯甲酸盐（25μg/d）或雌三醇（0.02mg/d）。3个月后，研究肾脏损伤指标（肾小球硬化指数和肾小管间质损伤指数）以及肾小球几何参数。采用免疫组织化学方法评估肾小球和肾小管间质中结蛋白、转化生长因子-β（TGF-β）、内皮素-1、IV型胶原、内皮型一氧化氮合酶以及雌激素受体α和β的表达。雌二醇和雌三醇对肾脏重量或血压无显著影响。雌二醇和雌三醇可显著降低蛋白尿（未处理的UNX/OVX动物，25.4±8.52mg/24h；雌二醇处理的UNX/OVX动物，15.37±6.12mg/24h；雌三醇处理的UNX/OVX动物，6.54±2.24mg/24h）。与未处理的动物（1.46±0.09）相比，雌三醇和雌二醇处理的动物肾小球硬化指数显著降低（雌二醇处理的UNX/OVX动物，0.69±0.16；雌三醇处理的UNX/OVX动物，0.21±0.12；P<0.05）；肾小管间质损伤指数呈现类似模式。雌激素处理的动物平均肾小球体积显著减小。在免疫组织化学、原位杂交和逆转录聚合酶链反应试验中，UNX/OVX动物的TGF-β和内皮素-1表达显著增加。这种增加被雌三醇消除，但未被雌二醇消除。同样，在UNX/OVX动物中观察到增殖细胞核抗原和IV型胶原在肾小球和肾小管间质中的表达显著升高，且雌三醇可降低其表达，但雌二醇无此作用。研究得出结论，在UNX自发性肾脏损伤模型中，雌三醇可减轻肾小球病变和肾小球肥大，而雌二醇的作用不太一致。同时，足细胞丢失、足细胞损伤证据（即结蛋白表达）以及肾小球损伤介质系统的表达均降低，表明雌三醇具有主要的肾脏保护作用。
