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.
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 VEGF165 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 VEGF165 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.
Wang
Ying
Y
Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Nagase
Sohji
S
Koyama
Akio
A
D000818:Animals; D003928:Diabetic Nephropathies; D005786:Gene Expression Regulation; D005919:Glomerular Filtration Rate; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D007678:Kidney Glomerulus / Q000166:cytology* / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D015854:Up-Regulation
D012333:RNA, Messenger; D009569:Nitric Oxide; D007334:Insulin-Like Growth Factor I; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019869:Phosphatidylinositol 3-Kinases