Matrix metalloproteinases and diabetic nephropathy

基质金属蛋白酶与糖尿病肾病

• 批准号: 6560945
• 负责人: KATHRYN M THRAILKILL
• 金额: $ 32.25万
• 依托单位: ARKANSAS CHILDREN'S HOSPITAL RES INST
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6560945
• 关键词: adolescence (12-20); albuminuria; basement membrane; biomarker; blood glucose; clinical research; diabetic nephropathy; disease /disorder proneness /risk; enzyme activity; extracellular matrix; glucose; glucose metabolism; growth factor; human subject; hyperglycemia; immunologic assay /test; insulin dependent diabetes mellitus; metalloendopeptidases; pathologic process; patient monitoring device; renal glomerulus; secretion; tissue inhibitor of metalloproteinases; young adult human (21-34)

DESCRIPTION (provided by applicant): Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that are involved in the breakdown and remodeling of extracellular matrix (ECM). Dysregulation of MMP activity has been implicated in many pathologic processes characterized by degradation of connective tissue matrices, including rheumatoid arthritis, periodontal disease and metastatic cancer. Recent studies both in vitro and in animal models of diabetes suggest that hyperglycemia-mediated alterations in MMP secretion, activation or action may also contribute to the development of diabetes-related complications including diabetic retinopathy and nephropathy. Based on these findings one can hypothesize that the mesangial accumulation and renal hypertrophy characteristic of diabetic nephropathy may result from reduced matrix degradation caused by a hyperglycemia-mediated suppression of renal MMP activity. In fact, preliminary clinical data from our laboratory confirm that in children with type 1 DM, serum MMP-2 concentrations are suppressed in the face of uncontrolled hyperglycemia, yet normalize with near-normalization of blood glucose levels. In the present study, we propose to investigate the hypothesis that MMPs are involved in the pathogenesis of diabetic nephropathy by measuring concentrations of specific MMPs (MMP-2, -8 and -9), concentrations of the naturally occurring inhibitors of MMPs (Tissue Inhibitor of Matrix Metalloproteinases, TIMP-1 and -2), and concentrations of the MMP-activated growth factor, insulin-like growth factor-I (IGF-I) in the serum and urine of patients with type 1 DM. We will examine levels of MMPs, TIMPs, and IGF-I in these biologic fluids among diabetic patient subgroups, ages 14-40 years, chosen to represent various time points in the natural history of d abet c nephropathy. Moreover, we will examine the correlation between observed differences in MMPFl'lMP/IGFconcentrations and differences in glycemic control at the time of study, as indicated by HbA1 c measurements and concurrent (72 hour) Continuous Subcutaneous Glucose Monitoring (CGMS). We anticipate that this study will provide preliminary evidence to establish a link between dysregulation of MMP activity and the pathogenesis of nephropathy in type 1 DM.

描述（由申请人提供）： 基质金属蛋白酶（MMPs）是一个锌依赖性蛋白酶家族，参与细胞外基质（ECM）的分解和重塑。MMP活性的失调与许多病理过程有关，这些病理过程的特征在于结缔组织基质的降解，包括类风湿性关节炎、牙周病和转移性癌症。最近在体外和糖尿病动物模型中的研究表明，高血糖介导的MMP分泌、活化或作用的改变也可能导致糖尿病相关并发症的发生，包括糖尿病视网膜病变和肾病。基于这些发现，可以假设糖尿病肾病的系膜积聚和肾脏肥大特征可能是由高血糖介导的肾脏MMP活性抑制引起的基质降解减少引起的。事实上，我们实验室的初步临床数据证实，在1型DM儿童中，血清MMP-2浓度在不受控制的高血糖面前受到抑制，但随着血糖水平接近正常化而正常化。在本研究中，我们建议通过测量特定MMPs的浓度来研究MMPs参与糖尿病肾病发病机制的假设（MMP-2、MMP-8和MMP-9），天然存在的MMP抑制剂的浓度（基质金属蛋白酶组织抑制剂，TIMP-1和TIMP-2），和MMP-活化生长因子的浓度，1型糖尿病患者血清和尿液中胰岛素样生长因子-I（IGF-I）的水平。我们将检测年龄在14-40岁的糖尿病患者亚组中这些生物液体中MMP、TIMP和IGF-I的水平，选择这些患者亚组代表糖尿病肾病自然史中的不同时间点。此外，我们将检查在研究时观察到的MMPF 1 - 1 MP/IGF浓度的差异和血糖控制的差异之间的相关性，如通过HbAlc测量和同时（72小时）连续皮下葡萄糖监测（CGMS）所指示的。我们预期这项研究将提供初步证据，以建立MMP活性失调和1型糖尿病肾病发病机制之间的联系。