Effects of glucose on matrix metalloproteinase and plasmin activities in mesangial cells: Possible role in diabetic nephropathy

• Published in: Kidney international Vol. 58; no. S77; pp. S81 - S87
• Main Authors: Mclennan, Susan V., Fisher, Elizabeth, Martell, Sally Y., Death, Alison K., Williams, Paul F., Lyons, J. Guy, Yue, Dennis K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2000; Elsevier Limited
• Subjects: Animals; Diabetic Nephropathies - etiology; diabetic nephropathy; Enzyme Activation; Fibrinolysin - physiology; Glomerular Mesangium - metabolism; Glucose - pharmacology; Humans; matrix degradation; matrix metalloproteinase; Matrix Metalloproteinases - genetics; Matrix Metalloproteinases - physiology; plasmin; Plasminogen - physiology; Tissue Inhibitor of Metalloproteinase-1 - physiology; Transcription, Genetic; Transforming Growth Factor beta - physiology; transforming growth factor-β; matrix metalloproteinase; matrix degradation; transforming growth factor-β; plasmin; diabetic nephropathy
• ISSN: 0085-2538; 0098-6577; 1523-1755
• DOI: 10.1046/j.1523-1755.2000.07713.x

Effects of glucose on matrix metalloproteinase and plasmin activities in mesangial cells: Possible role in diabetic nephropathy. Diabetic nephropathy is characterized by an accumulation of mesangium matrix that correlates well with the loss of kidney function. High glucose concentration is known to increase the synthesis of many matrix components. Recently, we have shown that degradation of matrix also decreases in diabetes. The major enzymes responsible for matrix degradation are the matrix metalloproteinases. The physiology of these enzymes is complex and their activity is tightly regulated at many levels. At the transcriptional level matrix metalloproteinase (MMP) expression is increased by protein kinase C (PKC) agonists, and some growth factors. In contrast transforming growth factor (TGF)-β can decrease MMP expression. Once synthesized, MMPs are secreted as inactive pro-enzymes that are activated by other MMPs or plasmin. To effect this, plasmin must be liberated from plasminogen in the pericellular environment. In turn, activated MMPs can be inhibited by binding to specific inhibitors known as tissue inhibitor of metalloproteinases (TIMP). Cell culture and animal studies have shown that high glucose (HG) decreases expression of MMPs and increases expression of TIMPs. HG can also affect MMP activation by decreasing plasmin availability and reducing expression of a membrane-bound MMP called MT1-MMP. How HG induces these changes remains to be fully elucidated. One possibility is that HG can increase TGF-β, which may in turn alter MMP promoter activity; this area is currently being studied in our laboratory.