Role of TGF-beta 1 in experimental glomerulonephritis.
Glomerulonephritis is an inflammation of the kidney characterized by the accumulation of extracellular matrix within the damaged glomeruli. We have shown that 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 addition of antiserum to TGF-beta 1. Conditioned media from glomerular cultures induced elevated proteoglycan synthesis when added to normal cultured mesangial cells. This stimulation was blocked by addition of TGF-beta antiserum. Glomerular histology showed mesangial matrix expansion with a time course that roughly paralleled that of the elevated proteoglycan synthesis by the nephritic glomeruli was increased. 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. 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.
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Division of Nephrology, University of Utah School of Medicine, Salt Lake City 84132.
Okuda
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Nakamura
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Languino
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Ruoslahti
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D000818:Animals; D000961:Antilymphocyte Serum / Q000633:toxicity; D002478:Cells, Cultured; D003470:Culture Media; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000187:drug effects / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D005353:Fibronectins / Q000096:biosynthesis; D005920:Glomerular Mesangium / Q000166:cytology; D005922:Glomerulonephritis, IGA; D015432:Glomerulonephritis, Membranoproliferative / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D007678:Kidney Glomerulus / Q000166:cytology; D011509:Proteoglycans / Q000096:biosynthesis; D051381:Rats; D013601:T-Lymphocytes; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*
D000961:Antilymphocyte Serum; D003470:Culture Media; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D011509:Proteoglycans; D016212:Transforming Growth Factor beta