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Role of transforming growth factor-beta 1 in experimental chronic cyclosporine nephropathy
F S Shihab1, T F Andoh, A M Tanner
1Division of Nephrology, University of Utah, Salt Lake City, USA.
Abstract:
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.
Insights
Chronic cyclosporine (CsA) nephropathy causes kidney fibrosis through transforming growth factor-beta 1 (TGF-β1). This study reveals CsA increases TGF-β1 and matrix proteins, driving kidney damage in rats.
Area of Science:
- Nephrology
- Renal Pathology
- Immunology
Background:
- The mechanisms underlying fibrosis in chronic cyclosporine (CsA) nephropathy are not fully understood.
- Transforming growth factor-beta 1 (TGF-β1) is implicated in the fibrotic processes of various kidney diseases.
Purpose of the Study:
- To investigate the role of TGF-β1 in the pathogenesis of chronic CsA nephropathy.
- To characterize the structural and functional changes in a rat model of CsA nephropathy.
Main Methods:
- A salt-depleted rat model was used, with rats treated with CsA or olive oil.
- Histological, physiological, and molecular analyses (mRNA expression, immunofluorescence) were performed at 7 and 28 days.
- Key markers included serum creatinine, creatinine clearance, enzymuria, concentrating ability, TGF-β1, matrix proteins, and plasminogen activator inhibitor.
Main Results:
- CsA-treated rats developed proximal tubular injury, tubulointerstitial fibrosis, and arteriolopathy by day 28.
- Physiological changes included elevated serum creatinine, reduced creatinine clearance, increased enzymuria, and impaired concentrating ability.
- Progressive increases in TGF-β1 and matrix protein mRNA expression were observed, particularly in the tubulointerstitial and vascular compartments, with medullary predominance.
Conclusions:
- The study suggests that TGF-β1 plays a significant role in the fibrotic process of chronic CsA nephropathy.
- CsA-induced kidney fibrosis appears to involve both the deposition and degradation pathways regulated by TGF-β1.
- The findings highlight the involvement of TGF-β1 and its downstream effectors in CsA-induced renal damage.