Matrix metalloproteinases and diabetic nephropathy

基质金属蛋白酶与糖尿病肾病

• 批准号: 6782491
• 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/6782491
• 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）：