Differential regulation of vascular endothelial growth factor and its receptor fms-like-tyrosine kinase is mediated by nitric oxide in rat renal mesangial cells

Under conditions associated with local and systemic inflammation, mesangial cells and invading immune cells are likely to be responsible for the relea se of large amounts of nitric oxide (NO) in the glomerulus. To further defi ne the mechanisms of NO action in the glomerulus, we attempted to identify genes which are regulated by NO in rat glomerular mesangial cells. We ident ified vascular endothelial growth factor (VEGF) and its receptor fms-like t yrosine kinase (FLT-1) to be under the regulatory control of exogenously ap plied NO in these cells. Using S-nitroso-glutathione (GSNO) as an NO-donati ng agent, VEGF expression was strongly induced, whereas expression of its F LT-1 receptor simultaneously decreased. Expressional regulation of VEGF and FLT-1 mRNA was transient and occurred rapidly within 1-3 h after GSNO trea tment. Expression of a second VEGF-specific receptor, fetal liver kinase-1 (FLK-1/KDR), could not be detected. The inflammatory cytokine interleukin-1 beta mediated a moderate increase in VEGF expression after 24 h and had no influence on FLT-1 expression. In contrast, platelet-derived growth factor -BE and basic fibroblast growth factor had no effect on VEGF expression, bu t strongly induced FLT-1 mRNA levels. Obviously, there is a differential re gulation of VEGF and its receptor FLT-1 by NO, cytokines and growth factors in rat mesangial cells.