Renin Angioensin Aldosterone System in Drub Abuse and HIV-associated Nephropathy

肾素血管紧张素醛固酮系统在药物滥用和 HIV 相关肾病中的作用

基本信息

批准号：
8118788
负责人：
PRAVIN C SINGHAL
金额：
$ 33.11万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8118788
关键词：
70-kDa Ribosomal Protein S6 Kinases AIDS-Associated Nephropathy African African American Aldosterone Aldosterone Antagonists Angiotensin-Converting Enzyme Inhibitors Angiotensinogen Animal Model Attenuated Data Development Dilatation - action Disease Disease model End stage renal failure Environmental Risk Factor Enzyme Inhibition Epithelial Epithelial Cells Focal glomerulosclerosis Gene Expression Generations Genes Genetic Goals HIV-1 Hospitalization Human In Situ Individual Infection Injury Integration Host Factors Kidney Kidney Diseases Lesion Mediating Mesenchymal Modeling Molecular Mouse Strains Mus Pathogenesis Pathway interactions Patients Peptidyl-Dipeptidase A Pharmacologic Substance Phenotype Play Population Production Rattus Renal Tissue Renin Renin-Angiotensin-Aldosterone System Reporting Research Research Personnel Role System Testing Transgenic Mice Tubular formation Variant aliskiren base cell injury eplerenone experience human FRAP1 protein inhibitor/antagonist kidney cell mRNA Expression podocyte prevent public health relevance receptor transdifferentiation vpr Genes

项目摘要

DESCRIPTION (provided by applicant): The renin- Angiotensin- Aldosterone System (RAAS) has been demonstrated to play an important role in the development and progression of renal lesions in both human and animal models of focal glomerulosclerosis (FGS). Interestingly, pharmaceutical agents which modulate the effects of Ang II have been the only ones investigated and proven to alter the course of HIV-associated nephropathy (HIVAN). Since inhibition of two other components of RAAS- eplerenone (a selective inhibitor of aldosterone) and aliskiren (a selective renin inhibitor) have also been reported to modulate the progression of renal lesions in non-HIVAN models of FGS, we hypothesize that use of these agents either alone or in combination with ACE (angiotensin I converting enzyme) inhibitors/AT1 receptor blockers will not only attenuate or prevent HIV-1-induced injury but also delay or slow down the progression of HIVAN. In preliminary studies, we observed that renal cells in mice transgenic HIV-1 genes (HIVAN mice, Tg26) not only showed activation of the mTOR pathway but also displayed enhanced epithelial mesenchymal transdifferentiation (EMT). Interestingly, aliskiren not only inhibited the activation of mTOR pathway as well as renal cell EMT but also attenuated HIVAN phenotype. Moreover, renal tissue of HIVAN (Tg26) mice showed six-fold increase in renin mRNA expression. These findings indicate that the activation of EMT and mTOR pathways in renal cells may be mediated either directly through renin or its downstream effector molecules such as Ang II. Since the activation of the RAAS (host factor) and or African descent (genetic factor) alone has not been shown to manifest into HIVAN phenotype in other renal disease models, it appears that manifestation of HIVAN phenotype requires specific environmental factors, such as renal cell expression of HIV-1 genes. Although, we can not change the ancestry but we can modulate the environmental (HIV-1 infection) and host factors. Based on our preliminary data, we hypothesize that modulation of RAAS by its selective inhibitors will not only prevent or attenuate HIV-1- induced renal injury but also delay or slow down the progression of HIVAN. PUBLIC HEALTH RELEVANCE: Patients infected with HIV-1 are prone to develop a rapidly progressing kidney disease termed HIV-associated nephropathy (HIVAN). HIVAN is the third leading cause of End-stage renal disease among individuals with African American background, and is associated with the highest rates of hospitalizations in this population. At present, there is no specific treatment to cure this disease. Since activation of Renin-Angiotensin- Aldosterone System plays an important role in the progression of renal diseases in general, we intend to evaluate the effect of its inhibition in HIVAN. Our long term research goal is to develop strategies to slow down the progression as well as find a cure of this devastating kidney disease.

描述（由申请人提供）：已证明肾素血管紧张素 - 醛固酮系统（RAAS）在局灶性肾小球硬化症（FGS）的人和动物模型中肾脏病变的发展和进展中起重要作用。有趣的是，调节ANG II作用的药物是唯一被调查并被证明可以改变与HIV相关的肾病（Hivan）的过程。 Since inhibition of two other components of RAAS- eplerenone (a selective inhibitor of aldosterone) and aliskiren (a selective renin inhibitor) have also been reported to modulate the progression of renal lesions in non-HIVAN models of FGS, we hypothesize that use of these agents either alone or in combination with ACE (angiotensin I converting enzyme) inhibitors/AT1 receptor blockers不仅会减弱或预防HIV-1诱导的损伤，而且还会延迟或减慢Hivan的进展。在初步研究中，我们观察到小鼠转基因HIV-1基因（Hivan小鼠，TG26）中的肾细胞不仅显示出MTOR途径的激活，而且显示出增强的上皮间质跨差异缩减（EMT）。有趣的是，Aliskiren不仅抑制了MTOR途径的激活以及肾细胞EMT的激活，而且还会减弱Hivan表型。此外，Hivan（TG26）小鼠的肾脏组织显示肾素mRNA表达增加了六倍。这些发现表明，肾细胞中EMT和MTOR途径的激活可以直接通过肾素或其下游效应分子（例如ANG II）介导。由于在其他肾脏疾病模型中尚未证明RAAS（宿主因子）和 /非洲血统（宿主因子）和 /非洲血统（遗传因子）的激活尚未表现为Hivan表型，因此Hivan表型的表现似乎需要特定的环境因素，例如HIV-1基因的肾细胞表达。虽然，我们无法改变祖先，但我们可以调节环境（HIV-1感染）和宿主因素。根据我们的初步数据，我们假设其选择性抑制剂对RAA的调节不仅会预防或减弱HIV-1诱导的肾损伤，而且还会延迟或减慢Hivan的进展。公共卫生相关性：感染HIV-1的患者容易发展为迅速发展的肾脏疾病，称为HIV相关肾病（Hivan）。 Hivan是具有非裔美国人背景的个体终末期肾脏疾病的第三大主要原因，并且与该人群的住院率最高有关。目前，还没有特定的治疗方法来治愈这种疾病。由于肾素 - 血管紧张素 - 醛固酮系统的激活在肾脏疾病的进展中起着重要作用，因此我们打算评估其抑制作用在Hivan中的影响。我们的长期研究目标是制定策略以减慢进展，并找到这种毁灭性肾脏疾病的方法。