STUDIES OF THE PATHOGENESIS OF GLOMERULOSCLEROSIS

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Most progressive glomerular diseases leading to endstage renal disease have increased extracellular matrix (ECM) within mesangial areas. Elucidation of the nature and the rate of ECM accumulation in diseased states are prerequisites for understanding, and possibly interfering with, progressive glomerulosclerosis. Changes in whole kidney preparations do not accurately reflect those in glomeruli. For these reasons we developed a technique consisting of microdissection of glomeruli, in situ RT of mRNA, and PCR. To quantitate changes in type IV collagen mRNA expression, we developed a competitive PCR assay. We first examined nephrectomies performed for renal carcinoma, since nearly 50% of these patients have glomerulosclerosis. We found that `2IV collagen cDNA was significantly elevated in patients with glomerulosclerosis. There was not a parallel increase in cell number, suggesting that the increment was due to upregulation of alpha2IV collagen mRNA, rather than cellular proliferation. As we found in mice, glomerular `2IV collagen cDNA level remained high, independently of the degree of sclerosis, even in patients who had extensive glomerular scarring. Satisfied that we had the appropriate tools to examine the pathogenesis of renal disease in humans, we started a multi-center collaboration to develop markers of progression. We obtained either cDNA or isolated microdissected glomeruli from diagnostic renal biopsies. The initial focus is on diabetes mellitus and IgA nephropathy. Our preliminary results indicate that the alpha2/alpha3 type IV collagen ratio is equal to 1 in normal kidneys, is high in diabetic nephropathy, and is 1 in membranous glomerulonephritis.