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Diet-induced hyperhomocysteinemia impairs vasodilation in 5/6-nephrectomized rats

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Abstract

Plasma homocysteine is elevated in patients with impaired renal function, and markedly so at end-stage renal disease. As chronic kidney disease and hyperhomocysteinemia are also independent risk factors for cardiovascular disease, the latter is hypothesized to accelerate vascular abnormalities following renal failure. This study aimed to investigate the combined effect of impaired renal function and hyperhomocysteinemia on vascular function. We show that in 5/6-nephrectomized rats, a model of chronic kidney disease, a methionine-rich diet for 8 weeks induces moderate hyperhomocysteinemia, exacerbates hypertension, and attenuates the vascular response to acetylcholine, sodium nitroprusside, 8-bromo-cGMP, and isoprenaline. However, plasma nitrate/nitrite and total NOS activity in the thoracic aorta were not affected. Collectively, the data imply that hyperhomocysteinemia and end-stage renal disease synergistically impair endothelium-dependent and endothelium-independent vasodilatation by blocking the cGMP/protein kinase G and/or cAMP/protein kinase A pathways. 5/6-Nephrectomized rat with hyperhomocysteinemia induced by a methionine-rich diet would be a useful model for elucidating the pathogenesis of vascular impairment in patients with end-stage renal disease.

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Funding

This work was supported in part by JSPS KAKENHI (Grant Numbers 26460207, 17K08428, 18K08224), National Basic Research Program of China (Grant Number 2015CB554405), and National Natural Science Foundation of China (Grant Number 81603335).

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Authors and Affiliations

  1. Institute of Basic Medical Sciences, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China

    Lei Li & JianXun Liu

  2. Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan

    Hiroshi Hasegawa & Kimiyoshi Ichida

  3. Center for Fundamental Laboratory Education, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan

    Niro Inaba

  4. Department of Public Health and Environmental Medicine, School of Medicine, The Jikei University, Tokyo, Japan

    Wataru Yoshioka

  5. National Institute of Complementary Medicine, School of Science and Health, Western Sydney University, Penrith, NSW, 2751, Australia

    Dennis Chang

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  1. Lei Li
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  2. Hiroshi Hasegawa
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  3. Niro Inaba
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  4. Wataru Yoshioka
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  5. Dennis Chang
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  6. JianXun Liu
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  7. Kimiyoshi Ichida
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Contributions

LL, HH, NI, and WY conceived and designed experiments. LL and HH performed experiments and analyzed data. LL, HH, JL, and DC prepared the manuscript; KI contributed reagents/material/analyses tools. All authors read and approved the final manuscript.

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Correspondence to Kimiyoshi Ichida.

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The authors declare that they have no conflict of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Handling Editor: H. Jakubowski.

Lei Li and Hiroshi Hasegawa are co-first authors.

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Li, L., Hasegawa, H., Inaba, N. et al. Diet-induced hyperhomocysteinemia impairs vasodilation in 5/6-nephrectomized rats. Amino Acids 50, 1485–1494 (2018). https://doi.org/10.1007/s00726-018-2626-3

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  • DOI: https://doi.org/10.1007/s00726-018-2626-3

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