title: Mechanism of fibrosis in experimental tacrolimus nephrotoxicity.
abstract: 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.
authors.affiliation: Division of Nephrology, University of Utah School of Medicine, Salt Lake City 84132, USA.
authors.forename: F S
authors.initials: FS
authors.lastname: Shihab
authors.forename: W M
authors.initials: WM
authors.lastname: Bennett
authors.forename: A M
authors.initials: AM
authors.lastname: Tanner
authors.forename: T F
authors.initials: TF
authors.lastname: Andoh
mesh_terms: 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
chemical_list: D016326:Extracellular Matrix Proteins; D017395:Plasminogen Activator Inhibitor 1; D017673:Sodium Chloride, Dietary; D019063:Tenascin; D016212:Transforming Growth Factor beta; D012083:Renin; D016559:Tacrolimus