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 language | English (US) |
---|---|
Pages (from-to) | 522-533 |
Number of pages | 12 |
Journal | Kidney International |
Volume | 63 |
Issue number | 2 |
DOIs | |
State | Published - 2003 |
Externally published | Yes |
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