Role of transforming growth factor-beta 1 in experimental chronic cyclosporine nephropathy.
The pathogenesis of fibrosis in chronic cyclosporine (CsA) nephropathy remains unknown. Since TGF-beta 1 plays a key role in the fibrogenesis of a number of renal diseases, we studied a salt-depleted rat model of chronic CsA nephropathy which shows similarity to the structural and functional lesions described in patients. Pair fed rats were treated with either CsA (15 mg/kg/day s.c.) or an equivalent dose of olive oil and sacrificed at 7 and 28 days. Characteristic histologic changes of proximal tubular injury, tubulointerstitial fibrosis and arteriolopathy developed in CsA-treated rats at day 28. They were accompanied by physiologic changes of increased serum creatinine, decreased creatinine clearance, increased enzymuria and decreased concentrating ability. CsA-treated rats showed a progressive increase in mRNA expression of TGF-beta 1 and matrix proteins at days 7 and 28. Most of the changes were in the tubulointerstitial and vascular compartments by immunofluorescence with a predominant involvement of the medulla as compared to cortex. The mRNA expression of plasminogen activator inhibitor, a protease inhibitor stimulated by TGF-beta 1, followed TGF-beta 1 and matrix proteins, suggesting that the fibrosis of chronic CsA nephropathy likely involves the dual action of TGF-beta on matrix deposition and degradation.
Shihab
F S
FS
Division of Nephrology, University of Utah, Salt Lake City, USA.
Andoh
T F
TF
Tanner
A M
AM
Noble
N A
NA
Border
W A
WA
Franceschini
N
N
Bennett
W M
WM
D000818:Animals; D001835:Body Weight; D002908:Chronic Disease; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000009:adverse effects*; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects; D007672:Kidney Cortex / Q000187:drug effects / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D007679:Kidney Medulla / Q000187:drug effects / Q000473:pathology; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000652:urine; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*
D016326:Extracellular Matrix Proteins; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D016572:Cyclosporine; D012964:Sodium; D003404:Creatinine