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Mechanism of fibrosis in experimental tacrolimus nephrotoxicity
F S Shihab1, W M Bennett, A M Tanner
1Division of Nephrology, University of Utah School of Medicine, Salt Lake City 84132, USA.
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.
Insights
Tacrolimus (FK506) causes kidney fibrosis through increased transforming growth factor-beta1 (TGF-beta1) and matrix proteins. This study investigates FK506 nephrotoxicity in a rat model, revealing TGF-beta1
Area of Science:
- Nephrology
- Immunology
- Pathology
Background:
- Tacrolimus (FK506) is a crucial immunosuppressant, but its clinical use is hampered by nephrotoxicity.
- The mechanisms underlying chronic FK506-induced kidney fibrosis are not fully understood.
- Transforming growth factor-beta (TGF-beta) is implicated in fibrosis in other nephrotoxic conditions.
Purpose of the Study:
- To investigate the role of TGF-beta1 and matrix protein expression in the pathogenesis of chronic FK506 nephrotoxicity.
- To characterize the histological and functional changes associated with FK506-induced nephropathy in a rat model.
- To explore the potential involvement of the renin-angiotensin system in FK506 nephrotoxicity.
Main Methods:
- A salt-depleted rat model was used, with rats treated with FK506 or vehicle.
- Kidney function and concentrating ability were assessed.
- Histological analysis and measurement of TGF-beta1, matrix proteins (biglycan, tenascin, fibronectin, type I collagen, type IV collagen), plasminogen activator inhibitor-1, and renin expression were performed at 7 and 28 days.
Main Results:
- FK506 treatment led to tubular injury, interstitial fibrosis, and arteriolopathy at 28 days, with impaired kidney function and enzymuria.
- Progressive increases in TGF-beta1 and specific matrix proteins (biglycan, tenascin, fibronectin, type I collagen) were observed in FK506-treated kidneys.
- Expression of plasminogen activator inhibitor-1 and both peripheral and tissue renin were elevated, suggesting a role for TGF-beta1 and the renin-angiotensin system in FK506 nephropathy.
Conclusions:
- Chronic FK506 nephrotoxicity in rats is characterized by interstitial fibrosis and arteriolopathy.
- TGF-beta1 and associated matrix protein deposition, along with plasminogen activator inhibitor-1, appear to drive fibrosis.
- The renin-angiotensin system may also contribute to the development of FK506-induced kidney damage.