Folic acid supplementation inhibits homocysteine‐induced superoxide anion production and chemokine expression in the kidney

Hyperhomocysteinemia, a condition of elevated blood homocysteine (Hcy) levels, is a metabolic disease. It is a common clinical finding in patients with chronic kidney diseases and occurs almost uniformly in patients with end-stage renal disease. Hyperhomocysteinemia is also a risk factor for cardiovascular disease. Our recent studies indicate that hyperhomocysteinemia can lead to renal injury by inducing oxidative stress. Oxidative stress is one of the important mechanisms contributing to Hcy-induced tissue injury. Folic acid supplementation is regarded as a promising approach for prevention and treatment of cardiovascular disease associated with hyperhomocysteinemia due to its Hcy-lowering effect. However, its effect on the kidney is not clear. The aim of this study was to examine the effect of folic acid supplementation on Hcy-induced superoxide anion production via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the kidney during hyperhomocysteinemia. Hyperhomocysteinemia was induced in male Sprague-Dawley rats fed a high-methionine diet for 12 wk with or without folic acid supplementation. A group of rats fed a regular diet was used as control. There was a significant increase in levels of superoxide anions and lipid peroxides in kidneys isolated from hyperhomocysteinemic rats. Activation of NADPH oxidase was responsible for hyperhomocysteinemia-induced oxidative stress in the kidney. Folic acid supplementation effectively antagonized hyperhomocysteinemia-induced oxidative stress via its Hcy-lowering and Hcy-independent effect. In vitro study also showed that 5-methyltetrahydrofolate, an active form of folate, effectively reduced Hcy-induced superoxide anion production via NADPH oxidase. Xanthine oxidase activity was increased and superoxide dismutase (SOD) activity was decreased in the kidney of hyperhomocysteinemic rats, which might also contribute to an elevation of superoxide anion level in the kidney. Folic acid supplementation attenuated xanthine oxidase activity and restored SOD activity in the kidney of hyperhomocysteinemic rats. These results suggest that folic acid supplementation may offer renal protective effect against oxidative stress.

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Folic acid inhibits homocysteine-induced superoxide anion production and nuclear factor kappa B activation in macrophagesThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigator's Forum.

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y05-136 ◽

2006 ◽

Vol 84 (1) ◽

pp. 141-147 ◽

Cited By ~ 45

Author(s):

Kathy K.W. Au-Yeung ◽

Johnny C.W. Yip ◽

Yaw L. Siow ◽

Karmin O

Keyword(s):

Folic Acid ◽

Nadph Oxidase ◽

Superoxide Anion ◽

Inflammatory Responses ◽

Nuclear Factor Κb ◽

Folic Acid Supplementation ◽

Nuclear Factor ◽

Superoxide Anion Production ◽

Monocyte Chemoattractant Protein 1 ◽

Acid Supplementation

Folic acid supplementation is a promising approach for patients with cardiovascular diseases associated with hyperhomocysteinemia. We have demonstrated that homocysteine (Hcy) activates nuclear factor-κB (NF-κB), a transcription factor that plays an important role in inflammatory responses. The aim of the present study was to investigate the effect of folic acid on Hcy-induced NF-κB activation in macrophages. Hcy treatment (100 μmol/L) resulted in NF-κB activation and increased monocyte chemoattractant protein-1 (MCP-1) expression in THP-1 derived macrophages. Hcy-induced NF-κB activation was associated with a significant increase in the intracellular superoxide anion levels. There was a significant increase in phosphorylation and membrane translocation of NADPH oxidase p47phox subunit in Hcy-treated cells. Addition of folic acid (200 ng/mL) to the culture medium abolished NADPH oxidase-dependent superoxide anion generation in macrophages by preventing phosphorylation of p47phox subunit. Consequently, Hcy-induced NF-κB activation and MCP-1 expression was inhibited. Such an inhibitory effect of folic acid was independent of its Hcy-lowering ability. Taken together, these results suggest that folic acid treatment can effectively inhibit Hcy-induced oxidative stress and inflammatory responses in macrophages. This may represent one of the mechanisms by which folic acid supplementation exerts a protective effect in cardiovascular disorders.

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