Role of Protein S in early Diabetic Kidney Disease

蛋白 S 在早期糖尿病肾病中的作用

• 批准号: 9134973
• 负责人: John Cijiang He
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 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 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9134973
• 关键词: Acetylation; Actins; Adhesions; Advanced Glycosylation End Products; Affect; Affinity; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Binding; Cell Proliferation; Cell Survival; Cells; Chronic; Code; Complications of Diabetes Mellitus; Cytoprotection; Cytoskeleton; Data; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Dialysis procedure; Disease; Disease Progression; Emotional; End stage renal failure; Endothelial Cells; Family; Foot Process; Funding; Gene Expression; Glomerulonephritis; Glucose; Healthcare; Histology; Human; Hypertrophy; In Vitro; Incidence; Incubated; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Insulin; Kidney; Kidney Diseases; Kidney Failure; Knock-out; Knockout Mice; Major Depressive Disorder; Measures; Mediating; Mus; Pathogenesis; Patients; Pharmaceutical Preparations; Plasma; Post-Traumatic Stress Disorders; Preventive; Progress Reports; Protein S; Proteins; Proteinuria; Proteomics; Quality of life; Receptor Protein-Tyrosine Kinases; Regulation; Renal function; Research; Role; STAT3 gene; Signal Pathway; Streptozocin; TNF gene; Testing; Therapeutic; Vascular Endothelial Growth Factors; Veterans; Wild Type Mouse; activated Protein C; angiogenesis; base; cell injury; cell motility; cofactor; diabetic; diabetic rat; in vivo; knock-down; mesangial cell; migration; mortality; mouse model; non-diabetic; novel; novel strategies; overexpression; patient population; podocyte; prevent; protective effect; public health relevance; receptor

 DESCRIPTION (provided by applicant): Project Summary Diabetic kidney disease (DKD) is the common cause of kidney failure. Elucidating mechanisms that mediate the early stage of DKD may help to identify novel preventive and therapeutic measures for patients with DKD. In the previous funding period, we demonstrated a critical role of NF-κB and STAT3 acetylation in DKD through the regulation of inflammatory gene expression (see progress report). To further understand the mechanism of early DKD injury, we performed proteomic studies in the glomeruli of streptozotocin (STZ)-induced diabetic rats and identified protein S (PS) as one of the proteins which were highly regulated in early DKD. PS, coded by Pros1, is a cofactor for the formation of activated protein C (APC). APC formation has been shown to protect glomerular cells from apoptosis in DKD. In addition, PS shares structural similarities with GAS6, which is known to be involved in the pathogenesis of kidney disease. Both PS and GAS6 bind to TAM receptors (Tyro3, Axl, and Mer), which belong to a family of receptor tyrosine kinases that mediates regulation of inflammation as well as cell survival and migration. However, PS and GAS6 have different binding affinity to individual TAM receptors and appear to have different functions. The role of PS and TAM receptors in kidney disease is not known. Our preliminary data suggest that PS expression increased in the glomeruli of diabetic rats and in human kidneys with early DKD, but decreased in those with advanced DKD. Plasma concentrations of PS were not different between diabetic and non-diabetic rats or humans, suggesting a local regulation of PS expression. We found that knockdown of PS in podocytes enhanced high glucose-induced apoptosis while overexpression of PS inhibited TNF-α-induced pro-inflammatory gene expression, suggesting a protective role of PS against diabetes-induced podocyte injury. We found that Tyro3, one of the TMA receptors, was upregulated by high glucose and knockdown of Tyro3 expression abolished the protective effects of PS in podocytes. Tyro3 expression is also upregulated in human glomeruli at early DKD but downregulated at late DKD. We developed podocyte-specific Pros1 knockout mice (KO) and found that diabetic KO mice developed more proteinuria, mesangial expansion, and foot process effacement than diabetic wild-type mice. Based on these findings, we hypothesize that PS may protect glomerular cell injury in early DKD through the formation of APC and/or effects mediated by Tyro3. We will test our hypothesis by two aims: In the aim 1, we will determine the factors which upregulate PS and Tyro3 at early DKD and those suppress PS and Tyro3 at late DKD and the effects of PS and Tyro3 in podocytes cultured in diabetic condition. In the aim 2 we will determine the role of PS and Tyro3 in DKD progression in vivo using both conditional overexpression and knockout mouse models for PS and Tyro3. We believe that the proposed studies could help us to elucidate the mechanism of glomerular cell injury in early DKD and therefore we could develop more effective drugs to prevent the progression of DKD.

 描述（由申请人提供）： 临床疾病（DKD）是肾脏衰竭的常见原因损伤，我们在链蛋白酶（STZ） - 染料糖尿病患者的肾小球上进行了蛋白质组学研究，并在早期DKD中高度调节了一种蛋白质（PS）。 DKD中凋亡的肾小球细胞，另外，PS的结构相似性与肾脏疾病的发病机理有关。介导的IND GAS6调节的激酶具有不同的bindidua toadua l tam受体，并且似乎具有不同的功能。在具有早期DKD的人类肾脏中基因表达，PS针对糖尿病诱导的Podocyte损伤的作用。 DKD早期的人肾小球，但在DKD晚期下调。可以保护dkd早期的肾小球损伤APC的形成和/或Tyro3介导的效果。和Tyro3在糖尿病状态下培养的足细胞。 DKD早期的肾小球细胞损伤，因此我们可以开发出更有效的DKDD药物。