Role of Gq Signaling in Promoting Podocyte Injury in Diabetes Mellitus

Gq 信号传导在促进糖尿病足细胞损伤中的作用

• 批准号: 8730134
• 负责人: Robert Spurney
• 金额: $ 34.15万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-09 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8730134
• 关键词: Americas; Angiotensin II Receptor; Animals; Apoptosis; Applications Grants; Attenuated; Calcium; Cell Line; Cell surface; Cells; Characteristics; Clinical; Complex; Complication; Coupled; Cre-LoxP; Developed Countries; Diabetes Mellitus; Diabetic Nephropathy; Disease; Disease Progression; Doxycycline; Economic Burden; Economics; End stage renal failure; Endocrine system; Endothelin; Epidemic; Etiology; G-Protein-Coupled Receptors; Genes; Genetic Models; Goals; Healthcare Systems; Human; In Vitro; Incidence; Injury; Inositol Phosphates; Insulin-Dependent Diabetes Mellitus; Kidney; Kidney Diseases; Mediator of activation protein; Medicare; Mus; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; PTGS2 gene; Pathogenesis; Patients; Phospholipase C; Phosphoric Monoester Hydrolases; Play; Population; Prostaglandins; Role; Second Messenger Systems; Series; Severities; Signal Pathway; Signal Transduction; Stem cells; System; Technology; Testing; Thromboxanes; Transgenic Mice; United States; base; cost; drug development; glomerulosclerosis; human MAPK14 protein; in vivo; inhibitor/antagonist; novel therapeutics; podocyte; prevent; promoter; receptor; regenerative; research study; rho GTP-Binding Proteins; second messenger; stress-activated protein kinase 1; therapeutic target; treatment strategy; type I and type II diabetes

DESCRIPTION (provided by applicant): Role of Gq signaling in promoting podocyte injury in diabetes mellitus: Diabetic nephropathy (DN) is the most common cause of end stage renal disease (ESRD) in developed countries. Accumulating evidence indicates that a reduced number of podocytes are 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. In turn, sufficient loss of podocytes leads to instability of the tuft and glomerulosclerosis. While the etiology of podocyte loss in DN is complex, a large body of evidence suggests that cell surface G protein coupled receptors (GPCRs) play an important, injury promoting role in DN including receptors for angiotensin II (ANGII), thromboxanes (TP), prostaglandins (EP1) and endothelins (ETA). Indeed, these GPCRs are expressed by glomerular podocytes and several of these receptor systems have been shown to promote podocyte injury both in vitro and in vivo. A common feature of these injury-promoting GPCRs is activation of Gq a-subunits (Gq). Activation of Gq and its downstream effectors might, therefore, be a final common signaling pathway that synergizes with other signaling cascades to promote podocyte injury in DN. In this regard, we found that Gq dependent CN activation promotes podocyte apoptosis, in part, by induction of the CN responsive gene COX2. Based on these observations, we hypothesized that Gq-coupled signaling cascades are important mediators of podocyte injury in DN by promoting podocyte apoptosis. To investigate this hypothesis, 3 specific aims are proposed. In specific aim #1, we have created transgenic (TG) mice that express either a constitutively activate Gq a-subunit (GqQ>L) or a Gq inhibitor (Gqi) specifically in glomerular podocytes using an inducible promoter system. We will use GqQ>L or Gqi TG mice to determine if either activating or inhibiting Gq, respectively, specifically in glomerular podocytes modulates the severity of kidney disease in a genetic model of type 1 diabetes (Akita mice). In specific aim #2, we will determine the signaling cascades activated by Gq that promote podocyte apoptosis in an immortalized podocyte cell line as well as in vivo. Lastly, in specific aim #3, we will create mice lacking COX2 specifically in podocytes and then determine the effects of podocyte specific COX2 deletion on podocyte apoptosis and glomerular damage in Akita mice. These studies will test the utility of inhibiting Gq signaling as a potential treatment strategy in DN and the role of podocyte COX2 expression in disease pathogenesis. If successful, the results may suggest novel therapeutic strategies for treating diabetic kidney disease.

描述（由申请人提供）：GQ信号传导在糖尿病中促进足细胞损伤中的作用：糖尿病性肾病（DN）是发达国家终末期肾脏疾病（ESRD）的最常见原因。积累的证据表明，足细胞数量减少是动物和糖尿病肾脏疾病的人的特征。由于足细胞是末端分化的细胞，其潜力很小，因此无法有效替换丢失的足细胞。反过来，足够的足细胞损失会导致簇和肾小球硬化的不稳定。虽然DN中足细胞损失的病因很复杂，但大量证据表明，细胞表面G蛋白偶联受体（GPCR）在包括血管紧张素II（Angii），Thlomboxanes（TP），Prostaglandins（Ep1）（EP1）和Endothelins（Eta）（ETA）（ETA）的DN中起着重要的损伤促进作用。实际上，这些GPCRs由肾小球足细胞表达，并且这些受体系统中的几个被证明可以在体外和体内促进足细胞损伤。这些促进损伤的GPCR的共同特征是GQ A-Subunits（GQ）的激活。因此，GQ及其下游效应子的激活可能是与其他信号级联协同作用的最终共同信号通路，以促进DN中的足细胞损伤。在这方面，我们发现依赖GQ的CN激活部分通过诱导CN响应基因COX2促进了足细胞凋亡。基于这些观察结果，我们假设通过促进足细胞凋亡，GQ耦合信号级联是DN中足细胞损伤的重要介质。为了研究这一假设，提出了3个具体目标。在特定的目标＃1中，我们创建了转基因（TG）小鼠，该小鼠要么使用诱导启动子系统在肾小球足细胞中专门在肾小球足细胞中专门在肾小球足细胞中特别激活GQ A-Subunit（GQQ> L）或GQ抑制剂（GQI）。我们将使用GQQ> L或GQI TG小鼠来确定分别在肾小球足细胞中分别激活或抑制GQ，在1型糖尿病（Akita小鼠）的遗传模型中调节肾脏疾病的严重程度。在特定的目标＃2中，我们将确定由GQ激活的信号传导级联反应，该级联促进了永生的足细胞系和体内的足细胞凋亡。最后，在特定的目标＃3中，我们将创建缺乏COX2的小鼠，专门在足细胞中，然后确定Podocyte特异性COX2缺失对Akita小鼠中足细胞凋亡和肾小球损伤的影响。这些研究将测试抑制GQ信号作为DN的潜在治疗策略以及足细胞COX2表达在疾病发病机理中的作用的实用性。如果成功，结果可能会表明治疗糖尿病肾脏疾病的新型治疗策略。

项目成果

Knockout of TRPC6 promotes insulin resistance and exacerbates glomerular injury in Akita mice.

• DOI: 10.1016/j.kint.2018.09.026
• 发表时间: 2019-02
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Liming Wang;Jae‐Hyung Chang;A. Buckley;R. Spurney

A novel role for type 1 angiotensin receptors on T lymphocytes to limit target organ damage in hypertension.

• DOI: 10.1161/circresaha.111.261768
• 发表时间: 2012-06-08
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Zhang JD;Patel MB;Song YS;Griffiths R;Burchette J;Ruiz P;Sparks MA;Yan M;Howell DN;Gomez JA;Spurney RF;Coffman TM;Crowley SD
• 通讯作者: Crowley SD