Matrix metalloproteinases and diabetic nephropathy

基质金属蛋白酶与糖尿病肾病

• 批准号: 6667115
• 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 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6667115
• 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 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)是一类锌依赖的蛋白酶家族，参与细胞外基质(ECM)的分解和重塑。基质金属蛋白酶活性的失调参与了以结缔组织基质降解为特征的许多病理过程，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上的研究表明，高血糖介导的基质金属蛋白酶分泌、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。根据这些发现，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脏基质金属蛋白酶活性抑制而导致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，面对无法控制的高血糖，血清基质金属蛋白酶-2浓度受到抑制，但随着血糖水平接近正常，血清基质金属蛋白酶-2浓度又恢复正常。在本研究中，我们建议通过检测1型糖尿病患者血清和尿液中特异性MMPs(MMPs-2、-8和-9)、自然产生的MMPs抑制物(TIMP-1和TIMP-2)以及血清和尿液中MMPs激活的生长因子、胰岛素样生长因子-I(IGF-I)的浓度来探讨MMPs参与糖尿病肾病发病机制的假设。我们将在14-40岁的糖尿病患者亚组中检测这些生物体液中MMPs、TIMPs和IGF-I的水平，这些亚组被选为代表糖尿病肾病自然病程中的不同时间点。此外，我们将研究观察到的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)所表明的。我们预期，这项研究将提供初步证据，以确定基质金属蛋白酶活性失调与1型糖尿病肾病发病机制之间的联系。