Associations of genetic variations in NEDD4L with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults

Ze-Jiaxin Niu, Shi Yao, Xi Zhang, Jian-Jun Mu, Ming-Fei Du, Ting Zou, Chao Chu, Yue-Yuan Liao, Gui-Lin Hu, Chen Chen, Dan Wang, Qiong Ma, Yu Yan, Hao Jia, Ke-Ke Wang, Yue Sun, Rui-Chen Yan, Zi-Yue Man, Dan-Feng Ren, Lan Wang, Wei-Hua Gao, Hao Li, Yong-Xing Wu, Chun-Hua Li, Ke Gao, Jie Zhang, Tie-Lin Yang, Yang Wang, Ze-Jiaxin Niu, Shi Yao, Xi Zhang, Jian-Jun Mu, Ming-Fei Du, Ting Zou, Chao Chu, Yue-Yuan Liao, Gui-Lin Hu, Chen Chen, Dan Wang, Qiong Ma, Yu Yan, Hao Jia, Ke-Ke Wang, Yue Sun, Rui-Chen Yan, Zi-Yue Man, Dan-Feng Ren, Lan Wang, Wei-Hua Gao, Hao Li, Yong-Xing Wu, Chun-Hua Li, Ke Gao, Jie Zhang, Tie-Lin Yang, Yang Wang

Abstract

Neural precursor cell expressed developmentally downregulated 4-like (NEDD4L), a member of the E3 ubiquitin-protein ligases, encoded by NEDD4L gene, was found to be involved in in salt sensitivity by regulating sodium reabsorption in salt-sensitive rats. The authors aimed to explore the associations of NEDD4L genetic variants with salt sensitivity, blood pressure (BP) changes and hypertension incidence in Chinese adults. Participants from 124 families in Northern China in the Baoji Salt-Sensitive Study Cohort in 2004, who received the chronic salt intake intervention, including a 7-day low-salt diet (3.0 g/day) and a 7-day high-salt diet (18 g/day), were analyzed. Besides, the development of hypertension over 14 years was evaluated. NEDD4L single nucleotide polymorphism (SNP) rs74408486 was shown to be significantly associated with systolic BP (SBP), diastolic BP (DBP) and mean arterial pressure (MAP) responses to low-salt diet, while SNPs rs292449 and rs2288775 were significantly associated with pulse pressure (PP) response to high-salt diet. In addition, SNP rs4149605, rs73450471, and rs482805 were significantly associated with the longitudinal changes in SBP, DBP, MAP, or PP at 14 years of follow-up. SNP rs292449 was significantly associated with hypertension incidence over the 14-year follow-up. Finally, this gene-based analysis found that NEDD4L was significantly associated with longitudinal BP changes and the incidence of hypertension over the 14-year follow-up. This study indicated that gene polymorphism in NEDD4L serve an important function in salt sensitivity, longitudinal BP change and development of hypertension in the Chinese population.

Trial registration: ClinicalTrials.gov NCT02734472.

Keywords: NEDD4L; gene polymorphism; hypertension; salt; salt sensitivity.

Conflict of interest statement

The authors declare that there is no conflict of interest.

© 2022 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.

References

    1. Olsen MH, Angell SY, Asma S, et al. A call to action and a lifecourse strategy to address the global burden of raised blood pressure on current and future generations: the Lancet commission on hypertension. Lancet. 2016;388(10060):2665‐2712.
    1. Petrie JR, Guzik TJ, Touyz RM. Diabetes, hypertension, and cardiovascular disease: clinical insights and vascular mechanisms. Can J Cardiol. 2018;34(5):575‐584.
    1. Padmanabhan S, Newton‐Cheh C, Dominiczak AF. Genetic basis of blood pressure and hypertension. Trends Genet. 2012;28(8):397‐408.
    1. Liu Y, Shi M, Dolan J, He J. Sodium sensitivity of blood pressure in Chinese populations. J Hum Hypertens. 2020;34(2):94‐107.
    1. He FJ, Tan M, Ma Y, MacGregor GA. Salt reduction to prevent hypertension and cardiovascular disease: JACC State‐of‐the‐Art Review. J Am Coll Cardiol. 2020;75(6):632‐647.
    1. Frisoli TM, Schmieder RE, Grodzicki T, Messerli FH. Salt and hypertension: is salt dietary reduction worth the effort. Am J Med. 2012;125(5):433‐439.
    1. Kelly TN, He J. Genomic epidemiology of blood pressure salt sensitivity. J Hypertens. 2012;30(5):861‐873.
    1. Luca CT, Crisan S, Cozma D, et al. Arterial hypertension: individual therapeutic approaches‐from DNA sequencing to gender differentiation and new therapeutic targets. Pharmaceutics. 2021;13(6):856.
    1. Rysz J, Franczyk B, Rysz‐Górzyńska M, Gluba‐Brzózka A. Pharmacogenomics of hypertension treatment. Int J Mol Sci. 2020;21(13):4709.
    1. Arnett DK, Claas SA, Glasser SP. Pharmacogenetics of antihypertensive treatment. Vascul Pharmacol. 2006;44(2):107‐118.
    1. Zhang Y, Qian H, Wu B, et al. E3 ubiquitin ligase NEDD4 family‑regulatory network in cardiovascular disease. Int J Biol Sci. 2020;16(14):2727‐2740.
    1. Manning JA, Kumar S. Physiological Functions of Nedd4‐2: lessons from knockout mouse models. Trends Biochem Sci. 2018;43(8):635‐647.
    1. Rougier JS, van Bemmelen MX, Bruce MC, et al. Molecular determinants of voltage‐gated sodium channel regulation by the Nedd4/Nedd4‐like proteins. Am J Physiol Cell Physiol. 2005;288(3):C692‐701.
    1. Donovan P, Poronnik P. Nedd4 and Nedd4‐2: ubiquitin ligases at work in the neuron. Int J Biochem Cell Biol. 2013;45(3):706‐710.
    1. Goel P, Manning JA, Kumar S. NEDD4‐2 (NEDD4L): the ubiquitin ligase for multiple membrane proteins. Gene. 2015;557(1):1‐10.
    1. Ishigami T, Kino T, Minegishi S, et al. Regulators of epithelial sodium channels in aldosterone‐sensitive distal nephrons (ASDN): critical roles of Nedd4L/Nedd4‐2 and salt‐sensitive hypertension. Int J Mol Sci. 2020;21(11):3871.
    1. Rotin D, Staub O. Nedd4‐2 and the regulation of epithelial sodium transport. Front Physiol. 2012;3:212.
    1. Ichimura T, Yamamura H, Sasamoto K, et al. 14‐3‐3 proteins modulate the expression of epithelial Na+ channels by phosphorylation‐dependent interaction with Nedd4‐2 ubiquitin ligase. J Biol Chem. 2005;280(13):13187‐13194.
    1. Minegishi S, Ishigami T, Kino T, et al. An isoform of Nedd4‐2 is critically involved in the renal adaptation to high salt intake in mice. Sci Rep. 2016;6:27137.
    1. Rizzo F, Staub O. NEDD4‐2 and salt‐sensitive hypertension. Curr Opin Nephrol Hypertens. 2015;24(2):111‐116.
    1. Ronzaud C, Loffing‐Cueni D, Hausel P, et al. Renal tubular NEDD4‐2 deficiency causes NCC‐mediated salt‐dependent hypertension. J Clin Invest. 2013;123(2):657‐665.
    1. Chen H, Ross CA, Wang N, et al. NEDD4L on human chromosome 18q21 has multiple forms of transcripts and is a homologue of the mouse Nedd4‐2 gene. Eur J Hum Genet. 2001;9(12):922‐930.
    1. Zhou R, Patel SV, Snyder PM. Nedd4‐2 catalyzes ubiquitination and degradation of cell surface ENaC. J Biol Chem. 2007;282(28):20207‐20212.
    1. Shi PP, Cao XR, Sweezer EM, et al. Salt‐sensitive hypertension and cardiac hypertrophy in mice deficient in the ubiquitin ligase Nedd4‐2. Am J Physiol Renal Physiol. 2008;295(2):F462‐470.
    1. Luo F, Wang Y, Wang X, Sun K, Zhou X, Hui R. A functional variant of NEDD4L is associated with hypertension, antihypertensive response, and orthostatic hypotension. Hypertension. 2009;54(4):796‐801.
    1. Dahlberg J, Nilsson LO, von Wowern F, Melander O. Polymorphism in NEDD4L is associated with increased salt sensitivity, reduced levels of P‐renin and increased levels of Nt‐proANP. PLoS One. 2007;2(5):e432.
    1. Araki N, Umemura M, Miyagi Y, et al. Expression, transcription, and possible antagonistic interaction of the human Nedd4L gene variant: implications for essential hypertension. Hypertension. 2008;51(3):773‐777.
    1. Wang Y, Chu C, Ren J, et al. Genetic variants in renalase and blood pressure responses to dietary salt and potassium interventions: a family‐based association study. Kidney Blood Press Res. 2014;39(5):497‐506.
    1. Chu C, Wang Y, Ren KY, et al. Genetic variants in adiponectin and blood pressure responses to dietary sodium or potassium interventions: a family‐based association study. J Hum Hypertens. 2016;30(9):563‐570.
    1. Du MF, Yao S, Zou T, et al. Associations of plasma uromodulin and genetic variants with blood pressure responses to dietary salt interventions. J Clin Hypertens (Greenwich). 2021;23(10):1897‐1906.
    1. Wang Y, Zhou Q, Gao WH, et al. Association of plasma cyclooxygenase‐2 levels and genetic polymorphisms with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults. J Hypertens. 2020;38(9):1745‐1754.
    1. Wang Y, Jia H, Gao WH, et al. Associations of plasma PAPP‐A2 and genetic variations with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults. J Hypertens. 2021;39(9):1817‐1825.
    1. Wang Y, Chu C, Wang KK, et al. Effect of Salt Intake on Plasma and Urinary Uric Acid Levels in Chinese Adults: an Interventional Trial. Sci Rep. 2018;8(1):1434.
    1. Hu JW, Wang Y, Chu C, et al. The responses of the inflammatory marker, pentraxin 3, to dietary sodium and potassium interventions. J Clin Hypertens (Greenwich). 2018;20(5):925‐931.
    1. Wang Y, Wang D, Chu C, et al. Effect of salt intake and potassium supplementation on urinary renalase and serum dopamine levels in Chinese adults. Cardiology. 2015;130(4):242‐248.
    1. Wang Y, Liu FQ, Wang D, et al. Effect of salt intake and potassium supplementation on serum renalase levels in Chinese adults: a randomized trial. Medicine (Baltimore). 2014;93(6):e44.
    1. Chu C, Wang Y, Wang M, et al. Common variants in serum/glucocorticoid regulated kinase 1 (SGK1) and blood pressure responses to dietary sodium or potassium interventions: a family‐based association study. Kidney Blood Press Res. 2015;40(4):424‐434.
    1. Staub O, Dho S, Henry P, et al. WW domains of Nedd4 bind to the proline‐rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome. EMBO J. 1996;15(10):2371‐2380.
    1. Kouremenos N, Zacharopoulou IV, Triantafyllidi H, et al. Genes and genetic variations involved in the development of hypertension: focusing on a Greek patient cohort. Hellenic J Cardiol. 2014;55(1):9‐16.
    1. Fava C, von Wowern F, Berglund G, et al. 24‐h ambulatory blood pressure is linked to chromosome 18q21‐22 and genetic variation of NEDD4L associates with cross‐sectional and longitudinal blood pressure in Swedes. Kidney Int. 2006;70(3):562‐569.
    1. Dahlberg J, Sjögren M, Hedblad B, Engström G, Melander O. Genetic variation in NEDD4L, an epithelial sodium channel regulator, is associated with cardiovascular disease and cardiovascular death. J Hypertens. 2014;32(2):294‐299.

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