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 matri x that correlates well with the loss of kidney function. High glucose conce ntration is known to increase the synthesis of many matrix components. Rece ntly, we have shown that degradation of matrix also decreases in diabetes. The major enzymes responsible for matrix degradation are the matrix metallo proteinases. The physiology of these enzymes is complex and their activity is tightly regulated at many levels. At the transcriptional level matrix me talloproteinase (MMP) expression is increased by protein kinase C (PKC) ago nists, and some growth factors. In contrast transforming growth factor (TGF )-beta call decrease MMP expression. Once synthesized, MMPs are secreted as inactive pro-enzymes that are activated by other MMPs or plasmin. To effec t this, plasmin must be liberated from plasminogen in the pericellular envi ronment. In turn, activated MMPs can be inhibited by binding to specific in hibitors known as tissue inhibitor of metalloproteinases (TIMP). Cell cultu re and animal studies have shown that high glucose (HG) decreases expressio n of MMFs and increases expression of TIMPs. HG can also affect MMP activat ion by decreasing plasmin availability and reducing expression of a membran e-bound MMP called MT1-MMP. How HG induces these changes remains to be full y elucidated. One possibility is that HG can increase TGF-beta, which may i n turn alter MMP promoter activity; this area is currently being studied in our laboratory.