Sustained expression of TGF-beta 1 underlies development of progressive kidney fibrosis.
We found that TGF-beta 1 expression and increased matrix production is transient and self-limited in nephritic glomeruli from rats with acute, reversible glomerulonephritis induced by a single injection of an antibody reactive with glomerular mesangial cells. In contrast, in rats given a second antibody injection, one week later, the glomerular expression of TGF-beta 1 mRNA and TGF-beta 1 protein remained elevated through 18 weeks and was associated with a large infiltration of mononuclear cells, with staining features of fibroblastic/myofibroblastic cells, strongly expressing TGF-beta 1 in the tubulointerstitium of the kidney. By 18 weeks kidneys from animals receiving two antibody injections showed glomerulosclerosis and tubulointerstitial fibrosis with striking deposition of collagens type I and III, whereas kidney tissue from animals given one antibody injection was indistinguishable from normal control. The histological changes were accompanied by persistent proteinuria and elevated levels of blood urea nitrogen. Extracellular matrix markers of TGF-beta 1 activity, a special isoform of fibronectin, tenascin, biglycan and plasminogen activator inhibitor-1, were significantly elevated in kidneys undergoing fibrosis. These data suggest that sustained TGF-beta 1 expression contributes to the development of progressive kidney fibrosis.
Yamamoto
T
T
Division of Nephrology, University of Utah School of Medicine, Salt Lake City.
Noble
N A
NA
Miller
D E
DE
Border
W A
WA
D000818:Animals; D015152:Blotting, Northern; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005455:Fluorescent Antibody Technique; D005920:Glomerular Mesangium / Q000378:metabolism / Q000473:pathology; D005921:Glomerulonephritis / Q000378:metabolism / Q000473:pathology; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D007668:Kidney / Q000473:pathology*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D012333:RNA, Messenger; D016212:Transforming Growth Factor beta