2-甲氧基雌二醇和2-乙氧基雌二醇减少老年肥胖糖尿病ZSF_1大鼠的肾疾病进展

2-Methoxyestradiol and 2-Ethoxyestradiol Retard the Progression of Renal Disease in Aged,Obese,Diabetic ZSF_1 Rats

目的检查2-ME和其一个合成类似物2EE(2-ETHOXYESTRADIOL)对高血压、肥胖和肾脏病进展的影响。方法:实验在35周肥胖ZSF_1大鼠中进行。动物分对照组(PEG-400,0.5μl/ h)和治疗组,2ME,2EE(18μg/kg/h),在0周,3,6和9周时分别测定代谢和肾功能,在9周时评价肾血流动力学和排泄功能。结果2ME,2EE对肥胖和高血压无作用,但可降低糖化血红蛋白和糖尿,防止时间依赖的蛋白尿的增加。2ME和2EE显著增加肾血流和肾小球滤过,减少肾血管阻力;免疫标记肾皮质标本,肥胖动物比同窝出生雄瘦动物有显示增加PCNA,NF-KAPPA B和VEGF的表达。2ME,2EE减少PCNA,NF-KAPPA B和VEGF的表达。结论雌二醇的非雌性激素的代谢物2ME和2EE,对代谢病和肥胖相关的肾病有直接的肾脏保护作用。

Objective The metabolic syndrome is a main cause for cardiovascular disease and for the accelerating epidemic of chronic renal failure. Previously we have demonstrated that 2-hydroxyestradiol （2HE）, an estradiol metabolite with little estrogenic activity, improves metabolic status and attenuates the development of renal disease in young, obese ZSF1 rats. In vivo, 2HE is readily converted to 2-methoxyestradiol （2ME）. The present study examined the effects of 2-methoxyestradiol （2ME） and the synthetic analog 2-ethoxyestradiol （2EE） on hypertension, obesity, and progression of renal disease in 35-week old, obese ZSF1 rats that fully expressed metabolic syndrome and progressive and severe nephropathy. Methods Animals were treated for 9 weeks with vehicle （PEG-400, 0.5 l/h）, 2-ME or 2-EE （18 g/kg/h）, metabolic and renal function were measured （Week 0, 3, 6 and 9）, and renal hemodynamics and excretory function were assessed （Week 9）. Results Obese animals had markedly glycosylated hemoglobin, glycosuria, hypertension and progressive overt proteinuria. 2ME and 2EE had no effects on obesity and hypertension, and reduced glycosylated hemoglobin and glucosuria and prevented time-dependent increase in proteinuria. 2ME and 2EE significantly increased renal blood flow and glomerular filtration, and reduced renal vascular resistance. Immunoblotting of renal cortical tissue samples revealed increased expression of PCNA, NF-kappa B and VEGF in obese animals compared to lean male littermates. 2ME and 2EE reduced the expression of PCNA, NF-kappaB and VEGF. Conclusions This study provides the first evidence that 2ME, a non-estrogenic metabolite of estradiol, and 2EE, a synthetic analog of estradiol metabolites, have direct renoprotective effects in nephropathy associated with metabolic syndrome and obesity.