Fructose increases the activity of sodium hydrogen exchanger in renal proximal tubules that is dependent on ketohexokinase

Takahiro Hayasaki, Takuji Ishimoto, Tomohito Doke, Akiyoshi Hirayama, Tomoyoshi Soga, Kazuhiro Furuhashi, Noritoshi Kato, Tomoki Kosugi, Naotake Tsuboi, Miguel A. Lanaspa, Richard J. Johnson, Shoichi Maruyama, Kenji Kadomatsu

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)


High fructose intake has been known to induce metabolic syndrome in laboratory animals and humans. Although fructose intake enhances sodium reabsorption and elevates blood pressure, role of fructose metabolism in this process has not been studied. Here we show that by ketohexokinase — the primary enzyme of fructose — is involved in regulation of renal sodium reabsorption and blood pressure via activation of the sodium hydrogen exchanger in renal proximal tubular cells. First, wild-type and ketohexokinase knockout mice (Male, C57BL/6) were fed fructose water or tap water with or without a high salt diet. Only wild type mice fed the combination of fructose water and high salt diet displayed increased systolic blood pressure and decreased urinary sodium excretion. In contrast, ketohexokinase knockout mice were protected. Second, urinary sodium excretion after intraperitoneal saline administration was reduced with the decreased phosphorylation of sodium hydrogen exchanger 3 in fructose-fed WT; these changes were not observed in the ketohexokinase knockout mice, however. Third, knockdown of ketohexokinase attenuated fructose-mediated increases of NHE activity with decreased cAMP levels in porcine renal proximal tubular cells (LLC-PK1). In conclusion, fructose metabolism by ketohexokinase increases sodium hydrogen exchanger activity in renal proximal tubular cells via decreased intracellular cAMP level, resulting in increased renal sodium reabsorption and blood pressure in mice.

Original languageEnglish
Pages (from-to)54-62
Number of pages9
JournalJournal of Nutritional Biochemistry
Publication statusPublished - 2019 Sept


  • Blood pressure
  • Fructose
  • Ketohexokinase
  • Kidney
  • NHE3
  • Sodium reabsorption

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Nutrition and Dietetics
  • Clinical Biochemistry


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