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 (MMP) 是锌依赖性蛋白酶家族，参与细胞外基质 (ECM) 的分解和重塑。 MMP 活性失调与许多以结缔组织基质降解为特征的病理过程有关，包括类风湿性关节炎、牙周病和转移性癌症。最近的体外和糖尿病动物模型研究表明，高血糖介导的 MMP 分泌、激活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，我们可以推测，糖尿病肾病的系膜积聚和肾脏肥大特征可能是由于高血糖介导的肾 MMP 活性抑制引起的基质降解减少所致。事实上，我们实验室的初步临床数据证实，在 1 型糖尿病儿童中，面对不受控制的高血糖，血清 MMP-2 浓度受到抑制，但随着血糖水平接近正常化而恢复正常。在本研究中，我们建议通过测量特定 MMP（MMP-2、-8 和 -9）的浓度、天然存在的 MMP 抑制剂（组织抑制剂）的浓度来调查 MMP 参与糖尿病肾病发病机制的假设。基质金属蛋白酶（TIMP-1 和 -2）的含量，以及患有以下疾病的患者血清和尿液中 MMP 激活的生长因子、胰岛素样生长因子-I (IGF-I) 的浓度1 型DM。我们将检查年龄为 14-40 岁的糖尿病患者亚组中这些生物液中 MMP、TIMP 和 IGF-I 的水平，这些亚组被选择代表糖尿病肾病自然史中的各个时间点。此外，我们将检查观察到的MMPF1'1MP/IGF浓度差异与研究时血糖控制差异之间的相关性，如HbA1c测量和同时（72小时）连续皮下血糖监测（CGMS）所示。我们预计这项研究将为建立 MMP 活性失调与 1 型糖尿病肾病发病机制之间的联系提供初步证据。