HORMONAL REGULATION OF ANGIOTENSIN RECEPTORS

一旦女性进入更年期，她们就失去了对高血压、心血管疾病和 进行性肾脏疾病与年龄匹配的绝经前女性和年龄匹配的男性相比。在……里面 在第一个资助期，我们发现通过摘除卵巢来实验性地模拟更年期状态 一些物种增加了肾上腺和肾脏中血管紧张素1型受体(ATIR)的密度，这 是肾素血管紧张素系统(RAS)的两个关键靶组织，对血液控制至关重要 压力。此外，增加的ATIR数量导致对血管紧张素II(Ang II)的敏感性增加。 这两种组织。在衰老和高血压相关肾脏疾病的病理模型中，雌激素 缺乏与肾脏损伤增加有关，包括间质纤维化和肾小球硬化， NAD(P)H氧化酶活性升高，这一作用可被17 P-雌二醇(？)2所阻止。我们也 最近发现，2缺乏降低了新发现的RAS成员的表达，即， 血管紧张素转换酶2(ACE2)，将血管紧张素转换酶II(Ang II)水解为血管扩张剂七肽(Ang-(L-T))。 ACE2的作用被认为与ACE2相反。事实上，ACE2已被证明具有心脏保护作用 在心脏；然而，关于ACE2在肾脏中的作用，人们知道的要少得多。 在这一竞争性更新中，我们将重点关注导致肾小管间质纤维化的信号通路。 (TIP)在小鼠单侧输尿管梗阻模型(UUO)，这是一种广泛使用的模型。 加速TIP。RAS在这些信号通路中发挥着重要作用，因为血管紧张素转换酶 血管紧张素转换酶抑制剂和血管紧张素受体拮抗剂在临床上被广泛用于抑制这些疾病的进展。 病理学。我们将研究ACE依赖(Aim1)、ATIR依赖(Aim 2)和 ACE2依赖(Aim 3)途径在导致TIP的病理过程中对肾脏有贡献 保护为雌激素充足的女性提供了保护。 在UUO的小鼠模型中，我们将检验以下假设：梗阻肾脏中的2丢失通过以下方式促进TIF 血管紧张素转换酶和血管紧张素转换酶依赖的超氧化物歧化酶增加肾脏氧化应激 血管紧张素转换酶依赖一氧化氮抑制超氧化物歧化的积累和减弱 (NO)生成；2丢失还通过以下方式刺激细胞外基质积累来促进TIP 依赖ACE和ATIR的转化生长因子β1(TGF-β1)-Smad信号通路增加。 导致TIPIN UUO的信号转导通路与许多慢性 各种原因引起的肾脏疾病。因此，专门研究RAS依赖的机制 2丢失对UUO患者TIP进展的潜在影响可能有助于更好地理解 参与绝经后妇女进行性肾病的机制，并最终可能导致 开发新的疗法来治疗这一男性和女性的主要公共卫生问题。

Once women enter menopause, they lose their protection from hypertension, cardiovascular disease and progressive renal disease when compared to age-matched premenopausal women and age-matched men. In the first funding period, we found that experimentally mimicking the state of menopause by ovariectomy in several species, increased the density of angiotensin type 1 receptors (ATiR) in the adrenal and kidney, which are two key target tissues of the renin angiotensin system (RAS) that are critical to the control of blood pressure. Furthermore, increased ATiR numbers resulted in increased sensitivity to angiotensin II (Ang II) in both these tissues. In pathological models of aging and hypertension associated renal disease, estrogen deficiency was associated with increased renal injury, including interstitial fibrosis and glomerulosclerosis, and increased NAD(P)H oxidase activity, which was prevented by 17p-estradiol (¿2) replacement. We also recently found that ¿2deficiency reduced the expression of the newly discovered member of the RAS,namely, angiotensin converting enzyme 2 (ACE2), which hydrolyzes Ang II to the vasodilator heptapeptide, Ang-(l-T). The actions of ACE2 are thought to counter those of ACE.In fact, ACE2 has been shown to be cardioprotective in the heart; however, much less is known regarding the role of ACE2 in the kidney. In this competitive renewal, we will focus on the signaling pathways leading to tubulointerstitial fibrosis (TIP) in the unilateral ureteral obstruction model (UUO) in the mouse, which is a widely used model of accelerated TIP.The RASplays a major role in these signaling pathways since angiotensin converting enzyme (ACE) inhibitors and ATiR antagonists are widely used clinically to inhibit disease progression in these pathologies. We will investigate ¿2 regulation of ACE-dependent (Aim1), ATiR-dependent (Aim 2) and ACE2-dependent (Aim 3) pathways in the pathological processes leading to TIP that contribute to the renal protection afforded the estrogen replete female. In a mouse model of UUO,we will test the hypothesis that ¿2 loss in the obstructed kidney promotes TIFby increasing renal oxidative stress through augmentation of ACE- and ATiR-dependent superoxide (Or) accumulation and attenuation of ACE2-dependent inhibition of superoxide accumulation through nitric oxide (NO) generation; ¿2 loss also promotes TIP by stimulating extracellular matrix accumulation through increased ACE-and ATiR-dependent transforming growth factor pi (TGF-pl)-Smad signaling pathways. The signal transduction pathways leading to TIPin UUO share many similarities with a number of chronic renal diseases of various etiologies. Thus, specifically investigating the RAS-dependent mechanisms underlying the effects of ¿2 loss on TIP progression in UUO may lead to a greater understanding of the mechanisms involved in progressive renal disease in postmenopausal women and ultimately, may lead to the development of novel therapeutics for treating this major public health problem in both men and women.