Li Hui, Jiang Tao, Lin Yifeng, Zhao Zhonghua, Zhang Nong
Department of Pathology, Shanghai Medical College, Fudan University, Shanghai, PR China.
Am J Nephrol. 2006;26(5):519-30. doi: 10.1159/000097368. Epub 2006 Nov 22.
Oxidative stress has been considered to be a common pathogenetic factor of diabetic nephropathy. Recent observations suggested that hepatocyte growth factor (HGF) was an antioxidant growth factor; thus, its renoprotective effects in diabetic nephropathy might be related to antioxidant mechanism. The aim of the present study was to evaluate whether HGF could prevent rat mesangial cells (RMC) from high-glucose-mediated oxidative stress and explore its relevant mechanism.
RMC were cultured in 5.6 mM (NG) or 30 mM (HG) glucose in the absence or presence of HGF (20 ng/ml) and c-met inhibitor SU11274 (5 microM) for 24 h.
c-met expression in HG was markedly increased. Enhanced oxidative stress was observed in HG as evidenced by elevated reactive oxygen species and malondialdehyde levels and decreased glutathione level, which was markedly attenuated by HGF. HGF also inhibited HG-induced p22(phox) and aldose reductase upregulation and prevented HG-reduced glutamate-cysteine ligase catalytic subunit (GCLC) expression through inhibiting USF binding to negative regulatory region of GCLC promoter. Reduced glucose-6-phosphate dehydrogenase activity and expression in RMC by HG was rescued by HGF.
HGF could function as an antioxidant factor and protect against HG-mediated oxidative stress by enhancing ROS scavenging and suppressing ROS production.
氧化应激被认为是糖尿病肾病常见的致病因素。最近的观察表明，肝细胞生长因子（HGF）是一种抗氧化生长因子；因此，其在糖尿病肾病中的肾脏保护作用可能与抗氧化机制有关。本研究的目的是评估HGF是否能预防大鼠系膜细胞（RMC）免受高糖介导的氧化应激，并探讨其相关机制。
RMC在5.6 mM（正常葡萄糖，NG）或30 mM（高糖，HG）葡萄糖中培养，分别在有无HGF（20 ng/ml）和c-met抑制剂SU11274（5 microM）的情况下培养24小时。
HG组中c-met表达明显增加。在HG组中观察到氧化应激增强，表现为活性氧和丙二醛水平升高以及谷胱甘肽水平降低，而HGF可明显减轻这种情况。HGF还抑制HG诱导的p22(phox)和醛糖还原酶上调，并通过抑制USF与GCLC启动子负调控区域的结合来防止HG降低的谷氨酸-半胱氨酸连接酶催化亚基（GCLC）表达。HGF可挽救HG导致的RMC中葡萄糖-6-磷酸脱氢酶活性和表达降低的情况。
HGF可作为一种抗氧化因子，通过增强活性氧清除和抑制活性氧产生来保护细胞免受HG介导的氧化应激。
