FIBROSE RENALE

Progressive glomerulosclerosis or interstitial fibrosis may occur in most chronic renal disorders and result in decreasing kidney function, eventuating in endstage renal failure. The pathogenesis of progressive renal disease is still largely unknown but there is considerable evidence that there is heterogeneity in the glomerular response to a sclerotic stimulus in the general population. For instance, in diabetes mellitus, despite similar levels of glycemia, only a fraction develops renal disease. The same is true for patients with AIDS nephropathy, where the propensity to the development of progressive glomerulosclerosis seems restricted to certain ethnic groups without regard to the severity of the underlying disease. The causes of this wide variation in response has led to the speculation that there may be an underlying genetic basis which determines the glomerular sclerotic response to particular stimuli. The normal glomerular extracellular matrix (ECM) contains multiple components, synthesized by the resident glomerular cells. The role of the mesangial cells, the smooth muscle component of the glomerulus, is critical in the development of glomerulosclerosis. Glomerular cells respond to various stimuli such as cytokines, or to metabolic derangements by an exaggerated synthesis of ECM, a phenomenon well established in vitro, and to a certain degree, in vivo. These data led us to evaluate the levels of ECM mRNAs in isolated microdissected glomeruli, in normal mice as well as in several models of glomerulosclerosis. We studied matrix synthesis at the level of gene expression and ECM composition in the intact glomerulus using a competitive PCR assay. To determine whether the rate of ECM synthesis and the composition of sclerosis were similar among diseases, we examined a normal mouse strain and compared them with transgenic mice or with strains which spontaneously developed glomerulosclerosis. Mice transgenic for growth hormone provide a good model of progressive glomerulosclerosis leading to terminal renal failure. In these mice, the levels of ECM matrix mRNA were elevated at all time points studied. The elevation occurred prior to the histologic appearance of glomerulosclerosis, and high mRNA levels persisted until the animal died in renal failure. We also examined these levels in a model of mouse which has a reduction in the number of glomeruli at birth (OS) and severe glomerulosclerosis, as well as in mice with more slowly progressive renal disease. The baseline levels of basement membrane collagen mRNAS varied between different mouse strains, and correlated with their propensity to develop glomerulosclerosis. In addition, the baseline ECM mRNA level predicted the subsequent outcome. Less is known about the factors that lead to interstitial fibrosis although it represents a critical determinant of renal fibrosis in human diseases. Three candidate cells can contribute to the excess of ECM in the interstitial compartment: fibroblasts, endothelial cells lining the interstitial capillaries and tubular cells.