HGF-mediated inhibition of oxidative stress by 8-nitro-cGMP in high glucose-treated rat mesangial cells

Abstract

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.

Keywords::

• hepatocyte growth factor
• oxidative stress
• mesangial cells
• reactive oxygen species
• 8-nitro-cGMP
• Nrf2

Acknowledgements

We thank Professor Takaaki Akaike, Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Japan, for kindly providing anti-8-nitro-cGMP monoclonal antibody 1G6.

Declaration of interest

This was supported for 3 years by grants from the National Natural Science Foundation of China (NSFC 30900538). The authors declared no conflicts of interests. The authors alone are responsible for the content and writing of the paper.