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

• 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
• 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

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.

项目摘要/摘要 在过去的几十年中，美国的糖尿病在美国急剧增加，并且迅速 成为我们医疗保健系统的主要挑战。许多糖尿病患者也是高血压（HT）， 这大大增加了糖尿病性肾病发展为末期肾脏疾病的风险 （ESRD）。临床和实验研究表明，降压治疗只会减慢进展 肾病到ESRD而不是停止。因此，迫切需要揭示机制 负责糖尿病性-HT肾病并确定新的治疗靶标。 II型的初步研究 糖尿病动物模型表明，即使在中度叠加时，BP也适度增加 糖尿病大大增强了肾脏损伤，这反映出蛋白尿显着增加和快速下降 GFR。另外，抑制内质网（ER）应激和清除活性氧 线粒体（MT）的（ROS）具有肾脏保护作用，表明ER应力和MT功能障碍 可能是导致HT加糖尿病协同作用的关键因素。也有证据表明 机械敏感的瞬态受体电势阳离子通道，亚家族C，成员6（TRPC6）可能具有 在糖尿病肾病中肾小球损伤发展中的重要作用。因此，它假设 II型糖尿病中HT和糖尿病的共存协同增强了氧化应激和细胞 肾小球的足细胞和内皮损伤。这种协同作用是由HT诱导的机械介导的 激活TRPC通道的拉伸，并通过ER应力，线粒体的相互作用进行扩增 功能障碍和CA2+稳态受损。在指导阶段，分子机制 高血压诱导的机械力与糖尿病相互作用以促进肾脏损伤 使用体外和体内模型。 HT和糖尿病对ER应激的分子途径的协同作用， 肾小球毛细管内皮细胞和足细胞中的线粒体功能障碍和TRPC6激活将是 也进行了评估。在独立阶段，TRPC6缺乏症对糖尿病的肾脏保护作用 HT肾脏损伤将使用新型的基因工程动物模型进行检查。这项研究的结果 将提供有关TRPC6通道在介导糖尿病-HT肾病中的作用的新信息。全面的， 该项目将促进申请人的持续技术，智力和专业培训，并将协助 在学术研究机构建立独立研究实验室的申请人。