STUDIES OF GLOMERULAR CELLS DERIVED FROM NORMAL AND TRANSGENIC MICE

肾小球硬化，细胞和细胞外基质周转增加

Glomerulosclerosis, increased cell and extracellular matrix turnover, is the leading cause of renal failure in the US. Current studies in models of glomerulosclerosis (GS) have yielded little information about the cellular abnormalities that are critical in the initiation and progression of this disease. This is due, in part, to the difficulty in isolating and characterizing glomeruli in vivo, and the fact that the glomerulus contains three indigenous cell types and a population of bone marrow-derived macrophages. This is particularly a problem with mice, a species we have chosen to study because of the availability of considerable genetic information. We have isolated the individual cell types and characterizing them in vitro. The first series of experiments examined the question of the phenotyPic modulation of glomerular mesangial cells in vitro, addressing the question of the effect of differing substrates, the time frame involved, and the molecular consequences of this modulation on extracellular matrix turnover. We found that mesangial cell proliferation and collagen mRNA levels are independently regulated. In addition, the nature of the matrix to which the cells adhered directly affected both proliferation and collagen mRNA levels. The second experiments addressed the handling of macromolecules by mesangial cells, since these cells are capable of ingesting immunoglobulins in vivo. The mannose receptor (MR), a carbohydrate binding membrane protein present on macrophages, was considered to be a candidate for the mechanism by which mesangial cells ingested these large proteins. The MR was found on mesangial cells which had been stimulated with either interleukin-1alpha or tumor necrosis factor-alpha.