Gene Nutrient Interactions in Kidney Function

肾功能中的基因营养相互作用

基本信息

批准号：
10066343
负责人：
LORRAINE J GUDAS
金额：
$ 45.77万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-04 至 2022-08-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10066343
关键词：
4 hydroxynonenal Acute Affect Agonist All-Trans-Retinol Area Biology CCL2 gene Cell Culture Techniques Cell Differentiation process Cell physiology Cells Chronic Kidney Failure Clinical Data Deposition Development Diabetic Nephropathy Diet Disease Disease model End stage renal failure Extracellular Matrix Family Fatty Liver Filtration Food Interactions Functional disorder Genes Genetic Genetic Models HIV High Fat Diet High Pressure Liquid Chromatography Histology Homeostasis Human Immune Immunohistochemistry Impaired Renal Function Inflammation Inflammatory Injury Injury to Kidney Kidney Kidney Diseases Kidney Failure Knock-out Knockout Mice Lead Lipids Liver X Receptor Manuscripts Measurement Methods Microalbuminuria Micronutrients Modeling Molecular Mus Nephrons New York City Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Nuclear Family Nuclear Receptors Obesity Outcome Oxidative Stress PPAR gamma Pathologist Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacology Population Positioning Attribute Postdoctoral Fellow Primary carcinoma of the liver cells Property Proteins Proteinuria Publications Publishing Reactive Oxygen Species Reagent Receptor Signaling Renal Replacement Therapy Renal carcinoma Renal function Renal tubule structure Renin-Angiotensin-Aldosterone System Research Research Personnel Retinoic Acid Receptor Retinoids Risk Factors SIRT1 gene SRE-1 binding protein Severities Smooth Muscle Actin Staining Method Specialist TLR4 gene TNF gene Testing Tretinoin Tubular formation Universities Vitamin A Work base cell type conditional knockout db/db mouse diet-induced obesity dietary drug efficacy efficacy study experience experimental study global health glomerular basement membrane glomerular filtration glomerulosclerosis high body mass index improved kidney cell kidney dysfunction kidney fibrosis medical schools member mesangial cell molecular targeted therapies mouse model new therapeutic target novel therapeutics obesity prevention obesity treatment podocyte pre-clinical prevent receptor receptor binding renal damage retinoic acid receptor alpha therapeutic target transcription factor

项目摘要

Chronic kidney disease (CKD) is quite common and often leads to end-stage renal disease (ESRD) with the resultant need for renal replacement therapy. Micro-albuminuria, proteinuria, hyper-filtration, and impaired renal function occur with obesity, suggesting that excess renal lipids, particularly free fatty acids (FFAs), may directly injure and/or indirectly damage the kidneys via increased oxidative stress and inflammation. An excess of renal lipids can damage renal tubule cells. Immune inflammatory pathways can induce oxidative stress, resulting in podocyte injury and protein deposition in the extracellular matrix of the nephron. Using two different murine models of renal disease associated with obesity, we have discovered that retinoic acid receptor β2 (RARβ2) agonists protect kidneys against lipotoxicity. RARβ2 is a member of a family of nuclear transcription factors that are activated by retinoids (derivatives and metabolites of vitamin A (retinol). We hypothesize that renal lipid accumulation is a key contributor to dysfunction in both the glomerular and tubular compartments and that this excess renal lipid accumulation can be prevented or reversed through the use of highly selective agonists of RARβ2. A corollary to this hypothesis is that renal dysfunction may be reversed by this RARβ2 agonist. We will test this hypothesis in three aims: in Specific Aim (1), we will test (in pre-clinical drug efficacy studies) selective RARβ2 agonists (AC261066, AC55649) to determine if these synthetic retinoids can (a) decrease the lipid deposition in the kidneys and (b) improve or stabilize kidney function in obesity-induced chronic kidney disease, indicating that these drugs could potentially be used to treat human patients who present with CKD associated with obesity. We will use two murine models, a high fat diet (HFD)-induced obesity model and db/db mice, a genetic model of obesity-associated CKD. In Specific Aim (2), we will explore the molecular mechanism(s) by which RARβ2 agonists reduce lipid accumulation and renal inflammation in these mouse models. Aim (2) will also test whether the RARβ2 agonists are acting via RARβ2 expressed in particular types of cells in the kidney through the use of renal cell type specific RARβ knockout mice. In Specific Aim (3), we will use cell culture models to ascertain if RARβ2 agonists act on podocytes, mesangial cells, and/ or proximal tubule cells via the RARβ2 receptor. Selective RARβ2 agonists have not been tested for treatment of obesity-induced CKD. Thus, our proposed research may define a specific, novel drug target and identify new drugs that treat, and even prevent obesity- associated nephropathy or, possibly, other types of CKD. The strengths of our application include our published work showing that the RARβ2 agonists inhibit the development of renal and hepatic steatosis in genetic and dietary obesity-induced murine disease models; the unique reagents in our possession, such as the conditional knockout RARβ mice; and our research team at Weill Cornell that includes researchers with considerable experience in retinoid pharmacology, mouse models, and renal histology and pathology.

慢性肾病 (CKD) 相当常见，常常导致终末期肾病 (ESRD)，从而需要肾脏替代治疗。肥胖会导致微量白蛋白尿、蛋白尿、过度滤过和肾功能受损。肾脏过量的脂质，特别是游离脂肪酸（FFA），可能会通过氧化应激和炎症增加而直接损伤和/或间接损害肾脏。肾脏脂质过量会损害肾小管细胞。炎症途径可诱导氧化应激，导致足细胞损伤和肾单位细胞外基质中的蛋白质沉积。通过使用与肥胖相关的两种不同的小鼠肾病模型，我们发现视黄酸受体 β2 (RARβ2) 激动剂可保护肾脏免受脂毒性。 RARβ2 是核转录因子家族的成员，可被类视黄醇（维生素 A（视黄醇）的衍生物和代谢物）激活。肾脂质蓄积是肾小球和肾小管室功能障碍的关键因素，并且可以通过使用高度选择性的 RARβ2 激动剂来预防或逆转这种过量的脂质肾蓄积，该假设的推论是肾功能障碍可以逆转。我们将在三个目标中测试这一假设：在特定目标 (1) 中，我们将测试（在临床前药物疗效研究中）选择性 RARβ2 激动剂。（AC261066，AC55649）以确定这些合成类视黄醇是否可以（a）减少肾脏中的脂质沉积，（b）改善或稳定肥胖引起的慢性肾病的肾功能，表明这些药物有可能用于治疗人类我们将使用两种小鼠模型，即高脂肪饮食 (HFD) 诱导的肥胖模型和 db/db 小鼠，即肥胖相关 CKD 的遗传模型。目标 (2)，我们将探索 RARβ2 激动剂减少这些小鼠模型中脂质积累和肾脏炎症的分子机制。目标 (2) 还将测试 RARβ2 激动剂是否通过特定类型细胞中表达的 RARβ2 发挥作用。在特定目标 (3) 中，我们将使用细胞培养模型来确定 RARβ2 激动剂是否作用于足细胞。肾小球膜细胞和/或近端肾小管细胞通过选择性 RARβ2 受体激动剂尚未测试用于治疗肥胖引起的 CKD。甚至可以预防肥胖相关肾病或其他类型的 CKD。我们的应用的优势包括我们已发表的研究成果，表明 RARβ2 激动剂可抑制肾脏和肝脏的发育。遗传和饮食肥胖引起的小鼠疾病模型中的脂肪变性；我们拥有的独特试剂，例如条件性敲除 RARβ 小鼠；以及我们在威尔康奈尔大学的研究团队，其中包括在类维生素A药理学、小鼠模型和肾脏组织学方面拥有丰富经验的研究人员和病理学。