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（申请人提供）：Gq信号在促进糖尿病足细胞损伤中的作用：糖尿病肾病（DN）是发达国家终末期肾病（ESRD）最常见的原因。越来越多的证据表明足细胞数量减少是糖尿病肾病动物和人类的一个特征。由于足细胞是终末分化的细胞，几乎没有增殖的潜力，因此失去的足细胞不能有效地补充。反过来，足细胞的充分损失导致簇的不稳定和肾小球硬化。虽然DN足细胞丢失的病因复杂，但大量证据表明，细胞表面G蛋白偶联受体（gpcr）在DN中起着重要的促进损伤作用，包括血管紧张素II （ANGII）、血栓素（TP）、前列腺素（EP1）和内皮素（ETA）受体。事实上，这些gpcr是由肾小球足细胞表达的，其中一些受体系统已被证明在体外和体内都能促进足细胞损伤。这些促进损伤的gpcr的一个共同特征是激活Gq A亚基（Gq）。因此，Gq及其下游效应物的激活可能是与其他信号级联协同促进DN足细胞损伤的最终共同信号通路。在这方面，我们发现Gq依赖的CN激活促进足细胞凋亡，部分是通过诱导CN应答基因COX2。基于这些观察，我们假设gq偶联信号级联通过促进足细胞凋亡是DN中足细胞损伤的重要介质。为了研究这一假设，提出了三个具体目标。在特定目标#1中，我们已经创建了转基因（TG）小鼠，这些小鼠使用诱导启动子系统在肾小球足细胞中特异性表达组成性激活Gq a亚基（GqQ>L）或Gq抑制剂（Gqi）。我们将使用GqQ>L或Gqi TG小鼠来确定在1型糖尿病遗传模型（秋田小鼠）中，激活或抑制肾小球足细胞中的Gq是否分别调节肾脏疾病的严重程度。在特定目标#2中，我们将确定Gq激活的信号级联，促进永生化足细胞细胞系和体内足细胞凋亡。最后，在特定目标#3中，我们将创建足细胞特异性缺乏COX2的小鼠，然后确定足细胞特异性COX2缺失对秋田小鼠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的潜在治疗策略的效用，以及足细胞COX2表达在疾病发病机制中的作用。如果成功，结果可能为治疗糖尿病肾病提供新的治疗策略。

项目成果

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

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