Stimulatory effect of IGF-I and VEGF on eNOS message, protein expression, eNOS phosphorylation and nitric oxide production in rat glomeruli, and the involvement of PI3-K signaling pathway

Abstract

Nitric oxide (NO) is reported to be involved in the pathogenesis of renal hyperfiltration in the early stage of diabetic nephropathy. We set out to determine whether IGF-I and/or VEGF 165 directly stimulate NO production in rat glomeruli and whether the expression of NO synthase (NOS) isoforms as well as eNOS phosphorylation contribute to NO generation by IGF-I and VEGF. Long-term exposure to IGF-I and/or VEGF 165 augments NO production through increased eNOS mRNA, protein expression and phosphatidylinositol 3-kinase (PI3-K) signaling pathway plays a major role in this process; short-term exposure to IGF-I and/or VEGF 165 activates eNOS activity via phosphorylation by a PI3-K/Akt dependent pathway. Our data suggest the great possibility that increased endogenous IGF-I and VEGF may be responsible for the up-regulation of eNOS expression and NO production which contributes to glomerular hyperfiltration in early diabetic kidneys. IGF-I is a newly described growth factor that up-regulates eNOS expression and PI3-K plays a major role in this process.