Diabetes mellitus is a major cause of renal morbidity and mortality. Approximately 25-40% of all patients with insulin dependent diabetes mellitus will develop clinical nephropathy. The constellation of the lesions of diabetic glomerulosclerosis associated with the clinical expression of this disorder is unique. The striking morphological feature is the expansion of the mesangial matrix which accounts for the increase in the mesangial volume fraction. This lesion is correlated with decreased capillary filtration surface and with albuminuria, hypertension and declining GFR. The mechanisms involved in the expansion of mesangial matrix are not known. In diabetic nephropathy, the deposition of fibronectin, laminin and type IV collagen is increased in the mesangium. Possible explanations for this increase include: Increased synthesis of matrix by mesangial cells; increased rate of incorporation of proteins into the matrix due to altered binding of matrix proteins to mesangial cells, decreased rates of degradation of matrix by mesangial cells or some combination of these three possibilities. We have found by immunocytochemistry, gel electrophoresis and solid phase ELISA that cultures of mesangial cells grown continuously for 4 weeks under conditions that mimic the diabetic environment (i.e., high glucose, 30 mM) display increased deposition of fibronectin, laminin, and type IV collagen similar to that reported in diabetic nephropathy in vivo. The objective of this proposal is to determine the mechanism(s) of this increased matrix deposition by mesangial cells grown in high glucose-containing medium.
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