Effect of nitric oxide modulation on TGF-beta 1 and matrix proteins in chronic cyclosporine nephrotoxicity

Background. Chronic cyclosporine (CsA) nephrotoxicity is characterized by i nterstitial fibrosis and afferent arteriolar hyalinosis. L-arginine (L-Arg) , the substrate for nitric oxide (NO) synthase and N-nitro-L-arginine-methy l ester (L-NAME), the NO synthase inhibitor, were shown to modulate acute C sA nephrotoxicity. However, the mechanism of fibrosis in chronic CsA nephro toxicity remains unclear. Thus, we examined the effect of NO modulation on fibrosis and the expression of transforming growth factor-beta 1 (TGF-beta 1) and matrix proteins in chronic CsA nephrotoxicity. Methods. Rats were administered CsA(7.5 mg/kg)lCsA; L-Arg (1.7 g/kg), CsA L-NAME (3.5 mg/kg), vehicle (VH), Vn + L-Arg, and VII + L-NAME? and were s acrificed at 7 or 28 days. NO production, physiologic parameters, and histo logy were studied in addition to the mRNA expression of TGF-beta 1, plasmin ogen activator inhibitor-1 (PAI-1) and the matrix proteins biglycan and col lagens type I and IV by Northern and the protein expression of PAI-1 and fi bronectin by enzyme-linked immunosorbent assay. Results. While L-NAME strikingly reduced NO biosynthesis and worsened the g lomerular filtration rate and CsA-induced fibrosis, L-Arg had the opposite beneficial effect. In addition. the CsA-induced up-regulated expression of TGF-beta 1, PAI-1, and the matrix proteins biglycan, fibronectin, and colla gen I was significantly increased with L-NAME and strikingly improved with L-Arg. Collagen IV expression was not affected. Also, NO modulation did not affect VH-treated rats. Conclusions. Chronic CsA nephrotoxicity can be aggravated by NO blockade an d ameliorated by NO enhancement, suggesting that NO maintains a protective function. NO modulation was associated with a change in TGF-beta 1 expressi on, which, in turn, was associated with alterations in matrix deposition an d matrix degradation through its effect on PAI-I.