Nitric oxide modulates vascular endothelial growth factor and receptors in chronic cyclosporine nephrotoxicity

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

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Background. Vascular endothelial growth factor (VEGF) is involved in angiogenesis, wound healing, and inflammation and exerts its effect via tyrosine kinase receptors, fms-like tyrosine kinase (Flt-1) and fetal liver kinase (Flk-1 or KDR). We have previously shown that VEGF is up-regulated in a model of chronic cyclosporine (CsA) nephrotoxicity and that L-arginine (L-Arg) improved while N-nitro-L-arginine-methyl ester (L-NAME) worsened fibrosis. We examined the role of nitric oxide modulation on VEGF in this model. Methods. Pair-fed salt-depleted rats were administered CsA, CsA + L-NAME, CsA + L-Arg, vehicle (VH), VH + L-NAME or VH + L-Arg and were sacrificed at 7 or 28 days. Physiologic and histologic changes were studied in addition to the mRNA expression of VEGF and its receptors Flt-1 and KDR/Flk-1 by Northern blot and the protein expression of VEGF by Western blot and immunohistochemical staining. Results. While L-NAME worsened renal function and histology, L-Arg had the opposite beneficial effect in CsA-treated rats. VEGF mRNA and protein expressions increased with CsA, further increased with L-NAME and became significantly reduced with L-Arg. Flt-1 expression was similar in all groups. On the other hand, KDR/Flk-1 mRNA expression was modulated in a fashion similar to VEGF. Also, nitric oxide modulation did not have an effect on VH-treated rats. Conclusions. VEGF expression in chronic CsA nephrotoxicity is increased by nitric oxide blockade and decreased by nitric oxide enhancement. Moreover, VEGF probably exerted its effect via the KDR/Flk-1 receptor. The actions of VEGF in this model remain speculative, but it is probable that VEGF plays a role, either independently or through nitric oxide, in CsA-induced fibrosis.

Original languageEnglish (US)
Pages (from-to)522-533
Number of pages12
JournalKidney International
Volume63
Issue number2
DOIs
StatePublished - 2003
Externally publishedYes

Keywords

  • Chronic nephrotoxicity
  • Cyclosporine
  • Fibrosis
  • Flt1-1
  • KDR/Flk-1
  • L-Arginine
  • L-NAME
  • Nitric oxide
  • Rats
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Nephrology

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