Role of Ovarian Senescence in End Stage Renal Disease

国家终末期肾病（ESRD）登记显示，许多肾脏疾病的进展在男性中比在年龄匹配的绝经前妇女中更具侵袭性。接受雌激素替代疗法（ERT）的绝经后妇女的肾脏疾病进展以及心血管疾病、骨质流失和认知功能的风险也比未接受ERT的妇女低得多。因此，肾脏内的激素反应可能与终末期肾病相关的危险因素有关。越来越多的证据表明雌激素对肾素血管紧张素系统有调节作用。我们拟在ESRD的5/6肾切除肾消融动物模型中探讨雌激素与肾素血管紧张素系统的相互作用。我们的第一个目的是确定17 - β -雌二醇（E2）对5/6肾切除大鼠进行性肾损伤指标的影响。我们拟测定E2对5/6切除卵巢（OVX）雌性大鼠的蛋白尿、血压、血尿氮、血清和尿肌酐以及肾小球硬化的剂量和时间依赖性，并将这些数据与年龄匹配的5/6切除卵巢（OVX）雄性大鼠和假手术动物进行比较。我们的第二个目的是确定E2对5/6肾切除大鼠肾血流动力学和ATE受体表达的影响。我们将确定E2对Ang II诱导的肾血流动力学变化的影响。我们将这些发现与E2对肾小球血管紧张素ATE受体(R)表达的影响联系起来。我们还将研究在Ang II输注和AT1受体阻断期间血管紧张素转换酶（ACE）抑制期间的这种相关性。我们假设雌激素可以保护肾功能，这是由观察到的进行性肾损伤决定因素的衰减和肾血流动力学的保存所证明的。我们还假设，在该动物模型中，雌激素降低AT受体表达的能力是雌激素肾保护作用的主要因素。这些研究可能会进一步揭示在肾脏病理进展中观察到的有充分记录的两性二态现象的机制，以及卵巢衰老中EDRD发病率增加的机制。

National end-stage renal disease (ESRD) registries have revealed that the progression of many renal diseases is more aggressive in men than it is in age-matched pre-menopausal women. The progression o renal disease as well as the risk for cardiovascular disease, bone loss and cognitive function is also much less in post-menopausal women on estrogen replacement therapy (ERT) compared to those without ERT. Thus, hormonal responses within the kidney may be involved in the risk factors associated with ESRD. There is accumulating evidence that estrogen has a regulatory influence on the renin angiotensin system. We propose to investigate the interaction of estrogen with the renin angiotensin system in the 5/6 nephrectomy renal ablation animal model of ESRD. Our first aim is to determine the effects of 17beta-estradiol (E2) on indicators of progressive renal injury in 5/6 nephrectomized rats. We propose to determine the dose and time dependency of E2 on proteinuria, blood pressure, blood urine nitrogen, serum and urine creatinine, and glomerulosclerosis in 5/6 nephrectomized ovariectomized (OVX) female rats and compare these data to aged matched 5/6 nephrectomized males and to sham operated animals. Our second aim is to determine the effects of E2 on renal hemodynamics and ATE receptor expression in 5/6 nephrectomized rats. We will determine the effects of E2 on Ang II- induced changes in renal hemodynamics. We will correlate these findings with the effects of E2 on glomerular angiotensin ATE receptor (R) expression. We will also examine this correlation during angiotensin converting enzyme (ACE) inhibition during Ang II infusion and AT1 receptor blockade. We hypothesize that estrogen will protect renal function as evidenced by an observed attenuation in determinants of progressive renal injury and in preservation of renal hemodynamics. We alsp hypothesize that the ability of estrogen to reduce AT, receptor expression is a major contributing factor in the renal protective effects of estrogen in this animal model. These studies may provide further insight into the mechanisms underlying the well-documented sexual dimorphism observed in the progression of renal pathology and in the increased incidence of EDRD with ovarian senescence.