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 在过去的几十年里，糖尿病在美国急剧增加，并迅速 成为我们医疗保健系统的主要挑战。许多糖尿病患者还患有高血压(HT)， 这大大增加了糖尿病肾病进展为终末期肾病的风险 (ESRD)。临床和实验研究表明，降压治疗只会减缓病情进展。 肾病对终末期肾病的作用而不是阻止它。因此，迫切需要揭示这些机制。 负责糖尿病-羟色胺肾病的治疗，并寻找新的治疗靶点。AII型的初步研究 糖尿病动物模型表明，当叠加到中度时，即使是适度的血压增加 糖尿病，极大地加剧了肾脏损害，反映在蛋白尿显著增加和 GFR。此外，抑制内质网(ER)应激和清除活性氧 线粒体(MT)产生的ROS具有肾脏保护作用，提示内质网应激和MT功能障碍 可能是高血压合并糖尿病协同作用的关键因素。也有证据表明 机械敏感的瞬时受体电位阳离子通道，C亚家族，成员6(TRPC6)可能有 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 高血压和糖尿病并存的II型糖尿病协同放大氧化应激和细胞 肾小球足细胞和内皮细胞损伤。这种协同效应是由高压氧诱导的机械作用所介导的 Stretch激活TRPC通道，并通过内质网应激、线粒体的相互作用而放大 功能障碍和钙稳态受损。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脏损伤将被确定 采用体外和体内模型。高血压与糖尿病在内质网应激分子通路中的协同作用 肾小球毛细血管内皮细胞和足细胞线粒体功能障碍和TRPC6激活 也进行了评估。在独立期，TRPC6缺乏对糖尿病患者肾脏的保护作用。 将使用新的基因工程动物模型来检查羟色胺肾损伤。这项研究的结果 将为TRPC6通道在介导糖尿病-羟色胺肾病中的作用提供新的信息。总的来说， 该项目将促进申请者的继续技术、智力和专业培训，并将有助于 在学术研究机构设立独立研究实验室的申请人。