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Synergistical effect of 20-HETE and high salt on NKCC2 protein and blood pressure via ubiquitin–proteasome pathway

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Abstract

We previously generated a cytochrome P450 4F2 (CYP4F2) transgenic mouse model and demonstrated that overexpressed CYP4F2 and overproduced 20-HETE in the kidneys contribute to the increase of blood pressure in the CYP4F2 transgenic mice with normal salt intake. We currently expect to elucidate a potential mechanism of salt-related hypertension whereby diverse levels of 20-HETE interact with dietary salt on Na+-K+-2Cl− cotransporter, isoform 2 (NKCC2) in the kidneys of the transgenic and wild-type mice with high salt intake. High salt intake reduced about 85 % abundance of renal NKCC2 protein in the transgenic mice and about 24 % in the wild-type mice by Western blot. Furthermore, we first found that NKCC2 was ubiquitinated and interacted with Nedd4-2 by immunoprecipitation in the transgenic mice with high salt intake. In addition, inhibition of 20-HETE synthesis or proteasome activity reversed the reduction of NKCC2 expression induced by 20-HETE and high salt intake. These results suggest that 20-HETE and high salt intake synergistically decrease the expression of NKCC2 protein via Nedd4-2-mediated ubiquitin–proteasome pathway, and thereby modulate natriuresis and blood pressure. We propose that diverse levels of 20-HETE have diverse effects on blood pressure in different salt concentrations.

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Acknowledgments

This study was supported by the ‘973’ Project of China (Grant No. 2009CB526401) and the national Natural Science Foundation of China (Grant No. 81070206).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Clinical Genetics, Shengjing Hospital of China Medical University, No. 36 San Hao Street, Shenyang, Liaoning, China

    Jingjing Wu, Xiaoliang Liu, Guangrui Lai & Yanyan Zhao

  2. Department of Medical Genetics, China Medical University, No. 92 Bei Er Road, Shenyang, Liaoning, China

    Jingjing Wu, Guangrui Lai & Yanyan Zhao

  3. Department of Pathology, Shengjing Hospital of China Medical University, No. 36 San Hao Street, Shenyang, Liaoning, China

    Xianghong Yang

  4. Department of Laboratory Animal Center, China Medical University, No. 92 Bei Er Road, Shenyang, Liaoning, China

    Luzeng Wang

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  1. Jingjing Wu
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  2. Xiaoliang Liu
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  3. Guangrui Lai
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  4. Xianghong Yang
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  5. Luzeng Wang
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  6. Yanyan Zhao
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Correspondence to Yanyan Zhao.

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Wu, J., Liu, X., Lai, G. et al. Synergistical effect of 20-HETE and high salt on NKCC2 protein and blood pressure via ubiquitin–proteasome pathway. Hum Genet 132, 179–187 (2013). https://doi.org/10.1007/s00439-012-1238-3

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  • DOI: https://doi.org/10.1007/s00439-012-1238-3

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