Department of Pathology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
Free Radic Res. 2012 Oct;46(10):1238-48. doi: 10.3109/10715762.2012.701292. Epub 2012 Jul 4.
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.
肝细胞生长因子（HGF）是治疗糖尿病肾病的一种有潜力的治疗剂。HGF 的肾保护作用机制已被广泛研究，但对糖尿病肾病中 HGF 的抗氧化信号知之甚少。我们的观察表明，在高葡萄糖（HG）处理的大鼠肾小球系膜细胞（RMC）中，一种硝化鸟嘌呤核苷酸，8-硝基鸟苷 3'5'-环单磷酸（8-nitro-cGMP）减少。然而，HGF 明显提高了细胞内 8-硝基-cGMP 水平，同时伴随着明显抑制氧化应激，表现为活性氧和丙二醛水平降低，谷胱甘肽水平升高。可溶性鸟苷酸环化酶（sGC）抑制剂 NS-2028 和一氧化氮合酶（NOS）抑制剂 l-NMMA 可以阻断 HGF 引起的 8-硝基-cGMP 水平升高和氧化应激抑制。因此，这两种抑制剂阻断了 HGF 诱导的核因子-E2 相关因子 2（Nrf2）的核积累和 Nrf2 下游谷氨酸-半胱氨酸连接酶催化亚基（GCLC）表达的上调。总之，HGF 通过增强一氧化氮和随后的 8-硝基-cGMP 产生，至少部分改善了 HG 介导的 RMC 氧化应激。
