Synergistic interactions of hypertension and diabetes in promoting kidney injury

高血压和糖尿病协同作用促进肾损伤

基本信息

批准号：
9295148
负责人：
Zhen Wang
金额：
$ 8.97万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
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：
2017-05-15 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9295148
关键词：
Animal Model Antihypertensive Agents Aortic coarctation Attenuated Blood Pressure Calcium Capillary Endothelial Cell Cations Clinical Research Data Development Diabetes Mellitus Diabetic Nephropathy Disease End stage renal failure Endothelial Cells Endothelium Fructose Functional disorder Genetic Engineering Glomerular Capillary Glucose Glucose Intolerance Goals Healthcare Systems High Fat Diet Homeostasis Hypertension Impairment In Vitro Injury Injury to Kidney Institution Insulin-Dependent Diabetes Mellitus Interruption Ion Channel Kidney Kidney Diseases Knockout Mice Laboratory Research Left kidney Link Mechanics Mediating Mentors Metabolic Mitochondria Modeling Molecular Non-Insulin-Dependent Diabetes Mellitus Oxidative Stress Pathway interactions Patients Phase Prevalence Proteinuria Rattus Reactive Oxygen Species Renal Hypertension Renal function Research Right kidney Risk Role Streptozocin Stretching Structure System Testing Therapeutic Training blood glucose regulation blood pressure reduction blood pressure regulation career development cell injury diabetic diabetic rat endoplasmic reticulum stress experimental study in vivo Model knockout animal knockout gene mechanical force member mitochondrial dysfunction new therapeutic target novel novel therapeutic intervention novel therapeutics podocyte protective effect receptor renal artery skills

项目摘要

PROJECT SUMMARY/ABSTRACT Diabetes mellitus has increased dramatically in the U.S. during the last several decades and has rapidly become a major challenge to our healthcare system. Many patients with diabetes are also hypertensive (HT), which substantially increases the risk for progression of diabetic nephropathy to end-stage renal disease (ESRD). Clinical and experimental studies indicate that antihypertensive treatment only slows the progression of nephropathy to ESRD rather than halting it. Therefore, there is an urgent need to reveal the mechanisms responsible for diabetic-HT nephropathy and to identify new therapeutic targets. Preliminary studies in a type II diabetic animal model indicate that even a moderate increase in BP, when superimposed on moderate diabetes, greatly enhances renal injury as reflected by significantly increased proteinuria and rapid decline in GFR. In addition, inhibition of endoplasmic reticulum (ER) stress and scavenging of reactive oxygen species (ROS) from mitochondria (MT) have renal protective effects, suggesting that ER stress and MT dysfunction may be key factors in contributing to the synergistic effects of HT plus diabetes. There is also evidence that mechanically sensitive transient receptor potential cation channels, subfamily C, member 6 (TRPC6) may have an important role in the development of glomerular injury in diabetic nephropathy. Therefore, it hypothesizes that coexistence of HT and diabetes in type II diabetes synergistically amplifies oxidative stress and cellular injury in podocytes and endothelium of glomeruli. This synergistic effect is mediated by HT-induced mechanical stretch which activates TRPC channels and is amplified by the interaction of ER stress, mitochondrial dysfunction and impaired Ca2+ homeostasis. During the mentored phase, the molecular mechanisms by which mechanical forces induced by hypertension interact with diabetes to promote renal injury will be determined using in vitro and in vivo models. Synergistic effects of HT and diabetes on molecular pathways of ER stress, mitochondrial dysfunction and TRPC6 activation in glomerular capillary endothelial cells and podocytes will be evaluated as well. During the independent phase, the renal protective effect of TRPC6 deficiency in diabetic- HT kidney injury will be examined using novel genetically engineered animal models. Results from this study will provide novel information on the role of TRPC6 channels in mediating diabetic-HT nephropathy. Overall, this project will facilitate applicant's continued technical, intellectual, and professional training, and will assist the applicant in establishing an independent research laboratory at an academic research institution.

项目概要/摘要过去几十年来，美国的糖尿病发病率急剧上升，并且发病率迅速上升成为我们医疗保健系统的重大挑战。许多糖尿病患者同时患有高血压（HT），这大大增加了糖尿病肾病进展为终末期肾病的风险（终末期肾病）。临床和实验研究表明，抗高血压治疗只会减缓病情进展肾病发展为终末期肾病（ESRD），而不是阻止它。因此，迫切需要揭示其机制负责糖尿病-HT 肾病并确定新的治疗靶点。 II型的初步研究糖尿病动物模型表明，即使血压中度升高，当叠加在中度血压上时糖尿病，大大加剧了肾损伤，表现为蛋白尿显着增加和肾功能迅速下降肾小球滤过率。此外，抑制内质网 (ER) 应激和清除活性氧来自线粒体 (MT) 的 (ROS) 具有肾脏保护作用，表明 ER 应激和 MT 功能障碍可能是促进 HT 与糖尿病协同作用的关键因素。还有证据表明机械敏感瞬时受体电位阳离子通道，C 亚族，成员 6 (TRPC6) 可能具有在糖尿病肾病肾小球损伤的发生发展中起重要作用。因此，它假设在 II 型糖尿病中，HT 和糖尿病共存会协同放大氧化应激和细胞足细胞和肾小球内皮细胞损伤。这种协同效应是由 HT 诱导的机械作用介导的拉伸激活 TRPC 通道，并通过 ER 应激、线粒体的相互作用而放大功能障碍和 Ca2+ 稳态受损。在指导阶段，分子机制高血压引起的机械力与糖尿病相互作用促进肾损伤将被确定使用体外和体内模型。 HT 和糖尿病对 ER 应激分子途径的协同作用，线粒体功能障碍和肾小球毛细血管内皮细胞和足细胞中 TRPC6 的激活将也评价了。在独立阶段，TRPC6 缺乏对糖尿病患者的肾脏保护作用将使用新型基因工程动物模型来检查 HT 肾损伤。这项研究的结果将提供有关 TRPC6 通道在介导糖尿病-HT 肾病中作用的新信息。全面的，该项目将促进申请人继续进行技术、智力和专业培训，并将协助申请人在学术研究机构建立独立的研究实验室。