Prevention of Renal Injury and Endothelial Dysfunction by Chronic l-Arginine and Antioxidant Treatment

Abstract

We evaluated the effects of vitamins with antioxidant properties (a combination of vitamins C and E) and l-arginine treatment on renal failure in mice by measuring survival rate. The molecular changes were elucidated by determining endothelial tetrahydrobiopterin (BH4) levels and nitric oxide synthase (eNOS) mRNA expression in mice with renal ablation. Previous studies have shown that endothelial dysfunction in 5/6 nephrectomized mice is associated with decreased nitric oxide (NO) bioavailability and increased vascular superoxide production. WTC57 mice were divided into three groups: Group 1 was the sham-operated group (C); Group 2 was the 5/6 nephrectomized group (Nfx); and Group 3 was a group of 5/6 nephrectomized mice, treated with l-arginine and vitamins with antioxidant properties (NfxTx; 200 mg/kg l-arginine, 83 mg/kg vitamin C, and 46.6 mg/kg vitamin E). After 20 weeks of treatment, urinary protein excretion, blood pressure, BH4 and dihydrobiopterin (BH2) levels, eNOS mRNA, oxidative stress, and survival rate were determined. An increase in urinary protein excretion, blood pressure, and oxidative stress was prevented in the NfxTx group, but not in the Nfx group. BH4 and eNOS mRNA expression was increased by 32% and 78%, respectively, in the NfxTx group. Furthermore, the treatment increased the survival rate by 33%. Our results indicate that under normal conditions, NO appears to protect renal function. However, this NO-dependent protection is lost during kidney failure, probably due to increased reactive oxygen species synthesis. The treatment restores the viability of NO and prevents the BH4 oxidation. Therefore, this treatment may represent a therapeutic approach for the management of kidney disease.

• kidney failure
• nitric oxide
• reactive oxygen species
• antioxidants
• endothelial dysfunction

Acknowledgments

Monica G. Arellano-Mendoza, Hilda Vargas-Robles, and Leonardo Del Valle-Mondragon designed the research; Monica G. Arellano-Mendoza, Hilda Vargas-Robles, and Bruno Escalante conducted the research; Monica G. Arellano-Mendoza and Amelia Rios analyzed data; and Monica G. Arellano-Mendoza and Bruno Escalante wrote the article and had primary responsibility for final content. All authors read and approved the final manuscript. We thank Fabiola Castorena for technical assistance. This project was supported by the Mexican Council of Science and Technology (CONACYT) as PhD Research Grant 81359 to Bruno Escalante.

We also thank Merck, México, for the donation of a new drug formulation containing a combination of antioxidants and l-arginine.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.