COLLAGEN AND COLLAGENASE MESSENGER-RNAS IN NORMAL AND SCLEROTIC GLOMERULI - PREDICTORS OF PROGRESSION AND RESPONSE TO THERAPY

Progressive glomerulosclerosis is associated with decreasing kidney fu nction, eventuating in end-stage renal failure. There are multiple com ponents of the extracellular matrix, and the exact composition in vari ous renal diseases is not known. Thus, we examined some of the major c omponents of the extracellular matrix (ECM) in murine and human glomer ular diseases. We studied matrix synthesis and degradation at the leve l of gene expression and ECM composition in the intact glomerulus. To determine whether the composition of sclerosis was similar among disea ses, we examined a normal mouse strain and compared it with strains wh ich spontaneously developed glomerulosclerosis. The baseline levels of matrix components varied between different mouse strains, and this le vel 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 glomerulosclero sis. Treatment with heparin substantially decreased the lesions withou t changes in type IV collagen mRNAs. However, there was an up-regulati on of both the mRNA and enzyme activity for the 92 kD matrix metallopr oteinase. In contrast, when these mice were treated with either angiot ensin converting enzyme inhibitors or angiotensin II (Ang II) receptor antagonists, the glomerulosclerosis was accentuated histologically an d the ECM synthetic and degradative mRNAs were elevated. These data su ggest that the mRNA levels reflect response to therapy. We examined gl omeruli from human nephrectomy specimens and found an increase in the mRNA levels for both the synthetic and degradative components of the E CM in those specimens with glomerulosclerosis. Preliminary examination of glomeruli isolated from renal biopsies reveals homogeneity in the alpha 2/alpha 3IV ratio among diabetics, but not among those with IgA nephropathy. These data suggest that modifications in ECM gene regulat ion may serve as predictors of progression.