MECHANISMS OF PROGRESSIVE RENAL DISEASE IN GLOMERULONEPHRITIS

Progressive renal disease in glomerulonephritis (GN) involves both glomerular and interstitial processes. In the glomerulus, sclerosis occurs with progressive accumulation of extracellular matrix components that reduce filtration surface area. In the interstitium, early inflammatory changes accompany GN with later development of fibrosis and tubular atrophy. Our studies have focused on the role of early cellular events in the development of glomerular and interstitial fibrosis. In the antithymocyte serum (ATS) model of mesangial proliferative GN, mesangial cell proliferation is initiated by processes involving complement and platelets and may involve basic fibroblast growth factor (bFGF). Mesangial cell proliferation is maintained by an autocrine mechanism involving upregulation of mesangial cell PDGF and PDGF receptors. Mesangial cells also change phenotype with expression of a-smooth muscle actin and production of type I collagen. These early changes precede upregulation of genes for the production of extracellular matrix components and the development of mesangial matrix expansion and sclerosis. Matrix expansion is reduced by factors that block cell proliferation, including platelet and complement depletion, heparin, and antibody to PDGF. A similar sequence of early platelet infiltration, increased expression of PDGF, and mesangial cell proliferation occurs early in the development of glomerulosclerosis in the remnant kidney model, and mesangial cell proliferation is a prominent early feature of experimental diabetic nephropathy. We believe these early glomerular cellular changes are linked to the later development of sclerosis. In the interstitium, acute GN is accompanied by upregulation of mRNA and protein for osteopontin, a macrophage chemotactic/adhesive factor expressed by cortical tubules following several types of glomerular injury. Interstitial macrophage localization occurs in areas of osteopontin expression followed by the development of interstitial fibrosis. These studies of early cellular events in the development of both glomerular and interstitial fibrosis may provide important clues to the mechanisms that underlie progressive renal disease in GN. © 1994, National Kidney Foundation. All rights reserved. All rights reserved.