HGF suppresses high glucose-mediated oxidative stress in mesangial cells by activation of PKG and inhibition of PKA
HGF suppresses high glucose-mediated oxidative stress in mesangial cells by activation of PKG and inhibition of PKA
复制标题
HGF 通过激活 PKG 和抑制 PKA 来抑制系膜细胞中高葡萄糖介导的氧化应激。
DOI：
10.1016/j.freeradbiomed.2010.05.002
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发表时间：
2010-08-01
影响因子：
7.4
通讯作者：
Nong, Zhang
中科院分区：
文献类型：
--
作者：
Hui, Li;Hong, Yu;Nong, Zhang
肝细胞生长因子（HGF）是一种有前景的药物，用于治疗各种肾脏疾病，包括糖尿病肾病，但其确切的作用机制仍有待阐明。我们以前已经证明，肝细胞生长因子保护大鼠肾小球系膜细胞（RMC）从高糖（HG）介导的氧化应激。本研究旨在探讨高糖诱导的氧化应激后HGF对RMC的保护作用。我们发现，无论是激动剂PKA毛喉素或拮抗剂PKG RP-8-pCPT-cGMPS部分衰减的抑制作用，肝细胞生长因子对HG增加RMC的氧化应激的活性氧和丙二醛水平升高和谷胱甘肽水平降低证明。此外，Rp-8-pCPT-cGMPS通过增强USF与GCLC启动子负调控区的结合，阻断了HG处理的RMC中HGF增加的谷氨酸-半胱氨酸连接酶催化亚基（GCLC）表达。毛喉素抑制HGF增加的葡萄糖-6-磷酸脱氢酶（G6PD）的活性和表达在RMC培养在HG。相应地，HGF抵消HG对PKA和PKG活性的影响。因此，PKA的抑制和PKG的激活参与了HGF的抗氧化作用。(C)2010年爱思唯尔公司All rights reserved.
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. (C) 2010 Elsevier Inc. All rights reserved.