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 fibrogenesi s of a number of renal diseases, we studied a salt-depleted rat model of chronic CsA nephropathy which shows similarity to the structural an d 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 oi l and sacrificed at 7 and 28 days. Characteristic histologic changes o f proximal tubular injury, tubulointerstitial fibrosis and arteriolopa thy developed in CsA-treated rats at day 28. They were accompanied by physiologic changes of increased serum creatinine, decreased creatinin e clearance, increased enzymuria and decreased concentrating ability. CsA-treated rats showed a progressive increase in mRNA expression of T GF-beta 1 and matrix proteins at days 7 and 28. Most of the changes we re in the tubulointerstitial and vascular compartments by immunofluore scence with a predominant involvement of the medulla as compared to co rtex. The mRNA expression of plasminogen activator inhibitor, a protea se inhibitor stimulated by TGF-beta 1, followed TGF-beta 1 and matrix proteins, suggesting that the fibrosis of chronic CsA nephropathy like ly involves the dual action of TGF-beta on matrix deposition and degra dation.