Role of Ovarian Senescence in End Stage Renal Disease

卵巢衰老在终末期肾病中的作用

• 批准号: 6334626
• 负责人: HONG JI
• 金额: $ 7.76万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6334626
• 关键词: aging; angiotensin receptor; angiotensins; blood pressure; cell senescence; chronic renal failure; disease /disorder model; estradiol; estrogens; glomerulosclerosis; hormone regulation /control mechanism; laboratory rat; ovary; peptidyl dipeptidase A; proteinuria; receptor expression

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.

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年龄匹配的绝经前女性更具侵袭性。接受雌激素替代治疗(ERT)的绝经后女性与未接受ERT的女性相比，肾脏疾病的进展以及心血管疾病、骨丢失和认知功能的风险也要低得多。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。本研究拟在终末期肾病5/6肾切除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。我们的第一个目标是确定17β-雌二醇(E_2)对5/6肾切除大鼠进行性肾损伤指标的影响。我们建议在5/6肾切除卵巢切除(OVX)的雌性大鼠上测定E2对蛋白尿、血压、血尿氮、血和尿肌酐以及肾小球硬化的剂量和时间依赖关系，并将这些数据与年龄匹配的5/6肾切除雄性大鼠和假手术动物进行比较。我们的第二个目标是确定E2对5/6肾切除大鼠肾脏血流动力学和ATE受体表达的影响。我们将确定雌二醇对血管紧张素转换酶II诱导的肾血流动力学改变的影响。我们将把这些发现与E2对肾小球血管紧张素受体(R)表达的影响联系起来。我们还将研究血管紧张素转换酶(ACE)在血管紧张素转换酶(ACE)输注期间的抑制和AT1受体阻断期间的这种相关性。我们假设雌激素将保护肾功能，观察到进行性肾损伤的决定因素的减弱和肾血流动力学的保存证明了这一点。我们还假设，雌激素降低AT1受体表达的能力是雌激素在该动物模型中发挥肾脏保护作用的主要因素。这些研究可能会进一步深入了解肾脏病理进展过程中观察到的有据可查的性别二型性现象的机制，以及随着卵巢衰老而导致的EDRD发生率的增加。