HGF-mediated inhibition of oxidative stress by 8-nitro-cGMP in high glucose-treated rat mesangial cells.
Hepatocyte growth factor (HGF) is a potential therapeutic agent for diabetic nephropathy. The mechanisms for the renoprotective effect of HGF have been studied extensively, but antioxidant signalling of HGF in diabetic nephropathy is minimally understood. Our observations indicated that a nitrated guanine nucleotide, 8-nitroguanosine 3'5'-cyclic monophosphate (8-nitro-cGMP) diminished in high glucose (HG)-treated rat mesangial cells (RMC). However, HGF obviously lifted intracellular 8-nitro-cGMP level, which was accompanied by remarkably suppressed oxidative stress as evidenced by decreased reactive oxygen species and malondialdehyde levels and elevated glutathione level. Inhibitor of soluble guanylyl cyclase (sGC) NS-2028 and inhibitor of nitric oxide synthase (NOS) l-NMMA could block increased 8-nitro-cGMP level and repress oxidative stress by HGF. Accordingly, these two inhibitors abrogated HGF-induced nuclear accumulation of NF-E2 related factor 2 (Nrf2) and up-regulation of Nrf2 downstream glutamate-cysteine ligase catalytic subunit (GCLC) expression. In conclusion, HGF ameliorated HG-mediated oxidative stress in RMC at least in part by enhancing nitric oxide and subsequent 8-nitro-cGMP production.
Department of Pathology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
Shang
S
Guoguo
Takaaki
T
Akaike
Jiang
J
Tao
Chen
C
Qi
Zhang
Z
Nong
Li
L
Hui
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D008315:Malondialdehyde / Q000378:metabolism; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase
C525106:8-nitroguanosine 3',5'-cyclic monophosphate; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D008315:Malondialdehyde; D017228:Hepatocyte Growth Factor; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D005978:Glutathione; D006152:Cyclic GMP; D005947:Glucose