Novel Targets for the Treatment of Diabetic Kidney Disease

治疗糖尿病肾病的新靶点

• 批准号: 9031226
• 负责人: Robert Spurney
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9031226
• 关键词: Adult; Albuminuria; Angiotensin II; Animals; Apoptosis; Apoptosis Regulation Gene; Apoptotic; Applications Grants; Attenuated; Calcineurin; Calcineurin inhibitor; Calcium; Cations; Cell Nucleus; Cells; Characteristics; Clinical; Complication; Cre-LoxP; Cytoplasm; Cytosol; Dependence; Diabetes Mellitus; Diabetic Nephropathy; Disease; Disease Progression; Economic Burden; Economics; End stage renal failure; Environment; Etiology; FK506; Focal Segmental Glomerulosclerosis; Gene Targeting; Genetic; Genetic Transcription; Goals; Healthcare Systems; Human; Hyperglycemia; Hypertension; In Vitro; Incidence; Injury; Insulin-Dependent Diabetes Mellitus; Ion Channel; Kidney; Kidney Failure; Knock-out; Mediating; Mediator of activation protein; Medical Economics; Messenger RNA; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Export; Nuclear Import; Pathogenesis; Patients; Peptides; Phosphotransferases; Play; Population; Preparation; Prevalence; Protein Isoforms; Proteinuria; Renal glomerular disease; Renin-Angiotensin System; Rodent; Role; Signal Pathway; Signal Transduction; System; T-Cell Activation; Technology; United States; Up-Regulation; Veterans; base; calcineurin phosphatase; diabetic; drug development; gain of function mutation; glomerulosclerosis; in vivo; interest; mouse model; new therapeutic target; non-diabetic; novel; novel strategies; nuclear factors of activated T-cells; podocyte; public health relevance; receptor; research study; therapeutic target; transcription factor; treatment strategy; type I and type II diabetes

 DESCRIPTION (provided by applicant): Diabetic nephropathy (DN) is the most common cause of end stage kidney disease (ESKD) in the United States. As a result, much effort has been devoted to understanding the mechanisms that promote glomerular damage in diabetic kidney disease. A large body of evidence suggests that glomerular podocytes play a pivotal role in the pathogenesis of DN. A reduced number of podocytes is a characteristic feature of both animals and humans with diabetic kidney disease. Because podocytes are terminally differentiated cells with little potential for proliferation, podocytes that are lost cannot be effectively replaced causing instability of glomerular tuft and promoting disease progression. While the etiology of podocyte loss is likely multifactorial, apoptosis is a prominent feature of diabetic kidney disease and is an important cause of podocyte loss in DN. A key regulator of apoptosis is intracellular calcium. Indeed, a large number of signaling pathways implicated in the pathogenesis of diabetic kidney disease increase intracellular calcium levels. Enhanced intracellular calcium levels activate downstream signaling pathways including the calcium activated phosphatase calcineurin (CN). Our lab has found that receptor systems that increase cytosolic calcium levels and stimulate CN activity promote podocyte apoptosis by mechanisms that are mediated by CN-dependent activation of NFAT (nuclear factor of activated T cells). An important gene target of CN signaling is the transient receptor potential cation channel C6 (TRPC6). These observations appear relevant to DN because: 1. TRPC6 is upregulated in a mouse model of type 1 diabetes (Akita mice), 2. The CN inhibitor FK506 attenuates podocyte apoptosis in Akita mice, and 3. Albuminuria is reduced in Akita mice lacking TRPC6. Based on these observations, we hypothesized that CN plays a key role in DN through mechanisms that involve up-regulation of TRPC6. To investigate this hypothesis, 3 specific aims are proposed. In specific aim #1, we will investigate the dynamic shuttling of NFAT isoforms between the cytosol and nucleus in cultured podocytes, which is dependent on the relative activity of CN phosphatases and NFAT kinases. The goal of these studies is to identify novel strategies for modulating CN- NFAT signaling in glomerular diseases. In specific aim #2, we will determine if the absence of TRPC6 inhibits podocyte apoptosis and reduces glomerular injury in Akita mice lacking TRPC6. In specific aim #3, we will determine if podocyte specific deletion of CN decreases podocyte apoptosis in DN and, in turn, ameliorates kidney injury in Akita mice. The long-term goal of the proposed studies is to identify novel therapeutic targets for the treatment of DN in humans.

 描述(由申请人提供)： 糖尿病肾病是美国终末期肾病最常见的病因。因此，人们一直致力于了解糖尿病肾病中促进肾小球损害的机制。大量证据表明，肾小球足细胞在糖尿病肾病的发病机制中起着关键作用。足细胞数量减少是患有糖尿病肾病的动物和人类的特征。由于足细胞是终末分化的细胞，几乎没有增殖的潜力，丢失的足细胞不能有效地被替代，导致肾小球绒毛不稳定，促进疾病进展。虽然足细胞丢失的病因可能是多因素的，但细胞凋亡是糖尿病肾病的一个显著特征，也是糖尿病肾病足细胞丢失的重要原因。细胞内钙是细胞凋亡的关键调节因子。事实上，在糖尿病肾病的发病机制中，大量的信号通路增加了细胞内的钙水平。升高的细胞内钙水平激活下游信号通路，包括钙激活的磷酸酶钙调神经磷酸酶(CN)。我们的实验室已经发现，增加胞浆钙水平和刺激CN活性的受体系统通过CN依赖的激活活化的T细胞核因子(NFAT)介导的机制促进足细胞凋亡。CN信号的一个重要基因靶点是瞬时受体电位阳离子通道C6(TRPC6)。这些观察结果似乎与糖尿病肾病有关，因为：1.TRPC6在1型糖尿病小鼠模型(秋田鼠)中上调，2.CN抑制剂FK506减少秋田鼠足细胞的凋亡，3.缺乏TRPC6的秋田鼠蛋白尿减少。基于这些观察，我们假设CN通过涉及TRPC6上调的机制在糖尿病肾病中发挥关键作用。为了验证这一假设，我们提出了三个具体目标。在特定的目标#1中，我们将研究NFAT亚型在培养的足细胞胞浆和胞核之间的动态穿梭，这取决于CN磷酸酶和NFAT激酶的相对活性。这些研究的目的是确定在肾小球疾病中调节CN-NFAT信号的新策略。在特定的目标#2中，我们将确定缺乏TRPC6是否会抑制足细胞的凋亡并减轻缺乏TRPC6的秋田小鼠的肾小球损伤。在特定的目标#3中，我们将确定CN的足细胞特异性缺失是否减少了糖尿病肾病患者的足细胞凋亡，进而改善了秋田小鼠的肾脏损伤。拟议研究的长期目标是确定治疗人类糖尿病肾病的新的治疗靶点。