HGF suppresses high glucose-mediated oxidative stress in mesangial cells by activation of PKG and inhibition of PKA.
Hepatocyte growth factor (HGF) is a prospective agent for therapy against a variety of nephrologic disorders including diabetic nephropathy, although the precise mechanisms for the effect of HGF remain to be elucidated. We have previously shown that HGF protects rat mesangial cells (RMC) from high glucose (HG)-mediated oxidative stress. In the present study, we focused on the pathway by which HGF exerts its protective effect on RMC after oxidative stress induced by high glucose. We show that either agonist of PKA forskolin or antagonist of PKG Rp-8-pCPT-cGMPS partly attenuated the inhibitory role of HGF on HG-increased oxidative stress in RMC as evidenced by elevated reactive oxygen species and malondialdehyde levels and decreased glutathione level. Moreover, Rp-8-pCPT-cGMPS blocked HGF-increased glutamate-cysteine ligase catalytic subunit (GCLC) expression in HG-treated RMC through enhancement of USF binding to the negative regulatory region of the GCLC promoter. Forskolin depressed HGF-increased glucose-6-phosphate dehydrogenase (G6PD) activity and expression in RMC cultured in HG. Correspondingly, HGF counteracted the effect of HG on PKA and PKG activity. Thus, inhibition of PKA and activation of PKG are involved in the antioxidant role of HGF.
Hui
Li
L
Department of Pathology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China. huili78@fudan.edu.cn
Hong
Yu
Y
Jingjing
Zhao
Z
Yuan
Huang
H
Qi
Chen
C
Nong
Zhang
Z
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D008315:Malondialdehyde / Q000378:metabolism; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D013873:Thionucleotides / Q000494:pharmacology
C090860:8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate; D000975:Antioxidants; D013873:Thionucleotides; D005576:Colforsin; D008315:Malondialdehyde; D017228:Hepatocyte Growth Factor; D005954:Glucosephosphate Dehydrogenase; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D005721:Glutamate-Cysteine Ligase; C544143:GCLC protein, rat; D005978:Glutathione; D006152:Cyclic GMP; D005947:Glucose