Mechanism of fibrosis in experimental tacrolimus nephrotoxicity.
The clinical use of tacrolimus (FK506) is limited by nephrotoxicity. The pathogenesis of fibrosis in chronic FK506 nephrotoxicity remains unknown. Because transforming growth factor (TGF)-beta plays a key role in the fibrogenesis of many diseases, including cyclosporine nephrotoxicity, we studied a salt-depleted rat model of chronic FK506 nephropathy in which clinically relevant FK506 blood levels are obtained and which shows similarities to the lesions described in patients receiving FK506. Pair-fed rats were treated with either FK506 (1 mg/kg/day s.c.) or an equivalent dose of vehicle and were killed at 7 or 28 days. Characteristic histologic changes of tubular injury, interstitial fibrosis, and arteriolopathy developed in FK506-treated rats at 28 days and were accompanied by worsening kidney function, decreased concentrating ability, and enzymuria. FK506-treated kidneys had a progressive increase in the expression of TGF-beta1 and matrix proteins (biglycan, tenascin, fibronectin, and type I collagen). This effect seems to be specific because the expression of type IV collagen, a basement membrane collagen, was not affected. Matrix deposition was present mostly in the tubulointerstitium and vessels in accordance with the FK506 chronic lesion. The expression of plasminogen activator inhibitor-1, a protease inhibitor influenced by TGF-beta, followed TGF-beta1 and matrix proteins, suggesting that the fibrosis of chronic FK506 nephropathy likely involves the dual action of TGF-beta1 on matrix deposition and degradation. Since both peripheral and tissue renin expression were elevated with FK506, the renin-angiotensin system may play a role in the pathogenesis of this condition.
Shihab
F S
FS
Division of Nephrology, University of Utah School of Medicine, Salt Lake City 84132, USA.
Bennett
W M
WM
Tanner
A M
AM
Andoh
T F
TF
D000818:Animals; D005109:Extracellular Matrix / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005355:Fibrosis / Q000139:chemically induced; D019084:Fluorescent Antibody Technique, Indirect; D015870:Gene Expression; D007672:Kidney Cortex / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D007679:Kidney Medulla / Q000473:pathology; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood / Q000378:metabolism; D017673:Sodium Chloride, Dietary; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D019063:Tenascin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016326:Extracellular Matrix Proteins; D017395:Plasminogen Activator Inhibitor 1; D017673:Sodium Chloride, Dietary; D019063:Tenascin; D016212:Transforming Growth Factor beta; D012083:Renin; D016559:Tacrolimus