The Role of Cyclooxygenase-2 in Podocyte Injury in Diabetic Nephropathy

环加氧酶2在糖尿病肾病足细胞损伤中的作用

• 批准号: 8195843
• 负责人: RAYMOND C. HARRIS
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195843
• 关键词: Ablation; Accounting; Adriamycin PFS; Adverse effects; Albuminuria; Angiotensin II; Animal Model; Awareness; Benefits and Risks; Blood Pressure; Blood Vessels; Caring; Cell Line; Cells; Characteristics; Clinical; Coxibs; Development; Diabetes Mellitus; Diabetic Nephropathy; Dialysis procedure; Disease; Economic Burden; End stage renal failure; Equilibrium; Experimental Animal Model; Fibrosis; Genetic; Genetically Engineered Mouse; Glucose; Goals; Health; Human; Hypertension; In Vitro; Individual; Inflammation; Injury; Kidney; Kidney Diseases; Knockout Mice; Lead; Link; Macula densa; Mediating; Mediator of activation protein; Medical; Modeling; Mus; Nephritis; Patients; Play; Population; Predisposition; Prevalence; Process; Production; Prostaglandin Inhibition; Prostaglandins; Proteinuria; Puromycin; Rattus; Reactive Oxygen Species; Renal function; Renal glomerular disease; Renin; Renin-Angiotensin System; Research Design; Risk; Role; Signal Transduction; Sodium Chloride; Source; Streptozocin; Structure; Syndrome; System; Testing; Transgenic Mice; Transplantation; United States; Up-Regulation; Veterans; Water; Wild Type Mouse; abstracting; cardiovascular risk factor; cell injury; clinically relevant; cyclooxygenase 2; diabetic; experience; hemodynamics; in vivo; inhibitor/antagonist; interstitial cell; overexpression; podocyte; prevent; prorenin receptor; protective effect; receptor; receptor upregulation; response; response to injury; salt sensitive; therapeutic development; therapeutic target

DESCRIPTION (provided by applicant): Project Summary/Abstract The podocyte is the primary glomerular cell targeted for injury during the development and progression of glomerular diseases that eventuate in end stage renal disease (ESRD). Renal expression of cyclooxygenase-2 (COX-2) increases in models of progressive renal injury, and selective COX-2 inhibitors decrease proteinuria and retard progressive renal injury in models of renal ablation, diabetes and salt- sensitive hypertension. However, the mechanisms by which inhibition of prostaglandin synthesis can ameliorate progressive renal injury remain undetermined. We propose that local expression of COX-2 in podocytes predisposes to progressive glomerular injury. We and others have demonstrated a selective increase of COX-2 expression in podocytes in models of progressive glomerular injury and found that over- expression of COX-2 in podocytes renders the glomerulus susceptible to adriamycin nephropathy. However, the mechanisms underlying COX-2 up-regulation in podocytes and potential roles in podocyte function in response to injury remain incompletely understood. We hypothesize increased podocyte COX-2 generates metabolites that interact with the local podocyte RAS, predisposing the podocyte to further injury in response to renal insults. The goal of these studies is to examine the potential role of prostaglandins as mediators and/or modulators of podocyte injury during the development of diabetic nephropathy. We propose two complementary specific aims. In Specific Aim I, we will investigate the role of altered COX-2 expression in podocyte injury during diabetic nephropathy in vivo, using genetically engineered mice that either selectively overexpress COX-2 or have genetic deletion of COX-2 in podocytes. We will also utilize mice with genetic deletions of specific prostanoid receptors to determine which prostaglandin(s) mediate podocyte injury and will elucidate interactions between podocyte COX-2 and the local podocyte renin-angiotensin system (RAS) during the development of diabetic nephropathy. In Specific Aim II, we will investigate the mechanisms by which COX-2 increases podocyte injury in response to high glucose in vitro using conditionally immortalized mouse podocytes from wild type mice, from the transgenic mice overexpressing COX-2 or null for COX-2 expression in podocytes. We will investigate the effects of high glucose on 1) the signals leading to increased podocyte COX-2 expression; 2) the effects of alterations in COX-2 expression on structure and function of differentiated podocytes in response to high glucose; and 3) the role of podocyte COX-2 as a mediator of increased production of ROS in podocytes. Although COX-2 inhibitors effectively ameliorate renal injury in animal models, the awareness of their potential to promote thrombotic vascular injury and to raise blood pressure preclude their clinical use in patients with progressive renal disease. Identification of which prostaglandins mediate glomerular injury and the determination of their mechanisms of injury may allow the development of therapeutic strategies with fewer potential side effects. PUBLIC HEALTH RELEVANCE: Project Narrative Over 20 million people in the United States have diabetes. Of these individuals, as many as one-third may develop diabetic nephropathy, the natural course of which can result in end stage renal disease (ESRD), as well as conferring markedly increased cardiovascular risks. Diabetes mellitus accounts for over 40% of percent of all new cases of ESRD making it the number one single disease requiring dialysis or transplantation in the United States. The economic burden of diabetes-related ESRD to U.S. medical care is estimated to be over $16 billion per year. The Veteran population is also at increased risk and the prevalence of diabetic nephropathy has skyrocketed it this population, with over 12% of the Veteran population served by the VA medical system now experiencing diabetes. The clinical syndrome of diabetic nephropathy (DN) is comprised of albuminuria, characteristic renal histopathologic changes and decreased renal function. Recent studies have identified the glomerular podocyte as both initiator and target of diabetic nephropathy. Our recent unpublished studies have suggested that prostaglandins derived from cyclooxygenase-2 (COX-2) expressed in the podocyte may be mediators of progressive podocyte injury in diabetic nephropathy. The current studies are designed to identify the prostaglandin(s) involved and elucidate mechanisms of injury. It is hoped that such studies may lead to targeted therapeutic options with a favorable risk-benefit profile that can prevent or slow the development of diabetic nephropathy.

描述（由申请人提供）： 足细胞是终末期肾病（ESRD）肾小球疾病发生发展过程中损伤的主要肾小球细胞。在进行性肾损伤模型中，环氧合酶-2（考克斯-2）的肾表达增加，并且选择性考克斯-2抑制剂在肾消融、糖尿病和盐敏感性高血压模型中减少蛋白尿并延缓进行性肾损伤。然而，抑制前列腺素合成可以改善进行性肾损伤的机制仍不确定。我们认为足细胞局部表达考克斯-2易导致进行性肾小球损伤。我们和其他人已经证明了在进行性肾小球损伤模型中足细胞中考克斯-2表达的选择性增加，并发现足细胞中考克斯-2的过度表达使肾小球对阿霉素肾病易感。然而，足细胞中考克斯-2上调的潜在机制和足细胞功能对损伤的反应仍不完全清楚。我们假设增加的足细胞考克斯-2产生的代谢产物与局部足细胞RAS相互作用，使足细胞在肾损伤后进一步损伤。这些研究的目的是检查在糖尿病肾病的发展过程中，胰高血糖素作为足细胞损伤的介质和/或调节剂的潜在作用。 我们提出了两个互补的具体目标。在特定目标I中，我们将研究考克斯-2表达改变在体内糖尿病肾病足细胞损伤中的作用，使用选择性过表达考克斯-2或足细胞中考克斯-2基因缺失的基因工程小鼠。我们还将利用特定前列腺素受体基因缺失的小鼠来确定哪种前列腺素介导足细胞损伤，并阐明糖尿病肾病发展过程中足细胞考克斯-2和局部足细胞肾素-血管紧张素系统（RAS）之间的相互作用。在特定目标II中，我们将研究考克斯-2增加足细胞损伤的机制，在体外使用条件永生化的小鼠足细胞从野生型小鼠，从转基因小鼠过表达考克斯-2或零考克斯-2表达的足细胞。我们将研究高糖对1）导致足细胞考克斯-2表达增加的信号的影响; 2）考克斯-2表达的改变对响应高糖的分化足细胞的结构和功能的影响;和3）足细胞考克斯-2作为足细胞中ROS产生增加的介体的作用。尽管考克斯-2抑制剂在动物模型中有效地改善肾损伤，但对其促进血栓性血管损伤和升高血压的潜力的认识排除了其在患有进行性肾病的患者中的临床使用。鉴定哪种洋地黄素介导肾小球损伤并确定其损伤机制可能允许开发具有更少潜在副作用的治疗策略。 公共卫生关系： 在美国有超过2000万人患有糖尿病。在这些个体中，多达三分之一的人可能发展为糖尿病肾病，其自然过程可导致终末期肾病（ESRD），以及赋予显著增加的心血管风险。糖尿病占所有新发ESRD病例的40%以上，使其成为美国需要透析或移植的头号疾病。糖尿病相关ESRD给美国医疗保健带来的经济负担估计每年超过160亿美元。退伍军人人口也处于增加的风险中，糖尿病肾病的患病率在这一人群中飙升，超过12%的退伍军人人口由VA医疗系统服务，现在患有糖尿病。糖尿病肾病（DN）的临床综合征包括蛋白尿、特征性肾组织病理改变和肾功能下降。近年来的研究发现，肾小球足细胞既是糖尿病肾病的始动者，也是糖尿病肾病的靶细胞。我们最近未发表的研究表明，来自足细胞中表达的环氧合酶-2（考克斯-2）的洋地黄素可能是糖尿病肾病进行性足细胞损伤的介质。目前的研究旨在确定涉及的前列腺素并阐明损伤机制。希望这些研究可能导致具有有利风险-效益特征的靶向治疗选择，可以预防或减缓糖尿病肾病的发展。