Collagen and collagenase mRNAs in normal and sclerotic glomeruli: Predictors of progression and response to therapy

Progressive glomerulosclerosis is associated with decreasing kidney function, eventuating in end-stage renal failure. There are multiple components of the extracellular matrix, and the exact composition in various renal diseases is not known. Thus, we examined some of the major components of the extracellular matrix (ECM) in murine and human glomerular diseases. We studied matrix synthesis and degradation at the level of gene expression and ECM composition of sclerosis was similar among diseases, we examined a normal mouse strain and compared it with strains which sponaneously developed glomerulosclerosis. The baseline levels of matrix components varied between different mouse strains, and this level correlated with their propensity to develop glomerulosclerosis. In addition, when glomerulosclerosis was induced, the baseline ECM mRNA level predicted the subsequent outcome. We studied mice transgenic for bovine growth hormone, since they develop progressive glomerulosclerosis. Treatment with heparin substantially decreased the lesions without changes in type IV collagen mRNAs. However, there was an up-regulation of both the mRNA and enzyme activity for the 93 kD matrix metalloproteinase. In contrast, when these mice were treated with either angiotensin converting enzyme inhibitors or angiotensin II (Ang II) receptor antagonists, the glomerulosclerosis was accentuated histologically and the ECM synthetic and degradative mRNAs were elevated. These data suggest that the mRNA level reflect response to therapy. We examined glomeruli from human nephrectomy specimens and found an increase in the mRNA levels for both the synthetic and degradative components of the ECM in those specimens with glomerulosclerosis. Preliminary examination of glomeruli isolated from renal biopsies reveals homogeneity in the α2/α3IV ratio among diabetics, but not among those with IgA nephropathy. These data suggest that modifications in ECM gene regulation may serve as predictors of progression.