Effect of nitric oxide modulation on TGF-β1 and matrix proteins in chronic cyclosporine nephrotoxicity

Fuad S. Shihab, Hong Yi, William M. Bennett, Takeshi F. Andoh

Research output: Contribution to journalArticlepeer-review

91 Scopus citations

Abstract

Background. Chronic cyclosporine (CsA) nephrotoxicity is characterized by interstitial fibrosis and afferent arteriolar hyalinosis. L-arginine (L-Arg), the substrate for nitric oxide (NO) synthase and N-nitro-L-arginine-methyl ester (L-NAME), the NO synthase inhibitor, were shown to modulate acute CsA nephrotoxicity. However, the mechanism of fibrosis in chronic CsA nephrotoxicity remains unclear. Thus, we examined the effect of NO modulation on fibrosis and the expression of transforming growth factor-β1 (TGF-β1) and matrix proteins in chronic CsA nephrotoxicity. Methods. Rats were administered CsA (7.5 mg/kg), CsA + L-Arg (1.7 g/kg), CsA + L-NAME (3.5 mg/kg), vehicle (VH), VH + L-Arg, and VH + L-NAME, and were sacrificed at 7 or 28 days. NO production, physiologic parameters, and histology were studied in addition to the mRNA expression of TGF-β1, plasminogen activator inhibitor-1 (PAI-1) and the matrix proteins biglycan and collagens type I and IV by Northern and the protein expression of PAI-1 and fibronectin by enzyme-linked immunosorbent assay. Results. While L-NAME strikingly reduced NO biosynthesis and worsened the glomerular filtration rate and CsA-induced fibrosis, L-Arg had the opposite beneficial effect. In addition, the CsA-induced up-regulated expression of TGF-β1, PAI-1, and the matrix proteins biglycan, fibronectin, and collagen 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 and ameliorated by NO enhancement, suggesting that NO maintains a protective function. NO modulation was associated with a change in TGF-β1 expression, which, in turn, was associated with alterations in matrix deposition and matrix degradation through its effect on PAI-1.

Original languageEnglish (US)
Pages (from-to)1174-1185
Number of pages12
JournalKidney International
Volume58
Issue number3
DOIs
StatePublished - 2000

Keywords

  • Afferent arteriolar hyalinosis
  • Collagen
  • Extracellular matrix
  • Fibrosis
  • Glycoprotein
  • L-arginine
  • Plasminogen activator inhibitor-1

ASJC Scopus subject areas

  • Nephrology

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