TRANSFORMING GROWTH FACTOR-BETA-1 INDUCES EXTRACELLULAR-MATRIX FORMATION IN GLOMERULONEPHRITIS

Extracellular matrices can be important in disease. Glomerulonephritis is an inflammation of the kidney that is characterized by the accumulation of extracellular matrix within the damaged glomeruli. We have shown that transforming growth factor-beta-1 (TGF-beta-1) is unique in regulating the production of proteoglycans and matrix glycoproteins by glomerular cells in vitro. In an experimental model of glomerulonephritis in rats, we found increased proteoglycan and fibronectin synthesis by cultured nephritic glomeruli, which was greatly reduced by the addition of antiserum to TGF-beta-1. Conditioned media from glomerular cultures, when added to normal cultured mesangial cells, induced elevated proteglycan synthesis. The stimulatory activity of the conditioned media was blocked by addition of TGF-beta-1 antheserum. Glomerular histology showed mesangial matrix expansion in a time course that roughly paralleled the elevated proteoglycan synthesis by the nephritic glomeruli. At the same time there was an increased expression of TGF-beta-1 mRNA and TGF-beta-1 protein in the glomeruli. Administration of anti-TGF-beta-1 at the time of induction of glomerulonephritis suppressed the elevated extracellular matrix production and dramatically attenuated histological manifestations of the disease. A small proteoglycan, decorin, also inhibits the activity of TGF-beta, potentially providing an alternative format for the prevention of TGF-beta activity. Our results provide direct evidence for a causal role of TGF-beta-1 in the pathogenesis of the experimental disease and suggest a new approach to the therapy of glomerulonephritis.