Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular cells

J Am Soc Nephrol. 2009 Mar;20(3):545-53. doi: 10.1681/ASN.2008060576. Epub 2009 Jan 21.


Increased consumption of fructose may play an important role in the epidemic of metabolic syndrome and may presage the development of diabetes, cardiovascular disease, and chronic kidney disease. Once in the cell, fructose is phosphorylated by ketohexokinase (KHK), leading to consumption of ATP, formation of AMP, and generation of uric acid through xanthine oxidoreductase (XOR). This study aimed to examine the direct effects of fructose in human kidney proximal tubular cells (HK-2) and whether they are mediated by the fructose metabolism via KHK. At a similar concentration to that observed in peripheral blood after a meal, fructose induced production of monocyte chemotactic protein 1 (MCP-1) and reactive oxygen species in HK-2 cells. Knockdown of KHK by stable transfection with small hairpin RNA demonstrated that these processes were KHK dependent. Several antioxidants, including specific inhibitors of NADPH oxidase and XOR, prevented MCP-1 secretion. We detected XOR mRNA in HK-2 cells and confirmed its activity by identifying uric acid by mass spectrometry. Fructose increased intracellular uric acid, and uric acid induced production of MCP-1 as well. In summary, postprandial concentrations of fructose stimulate redox- and urate-dependent inflammatory mediators in proximal tubular cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Base Sequence
  • Cell Line
  • Chemokine CCL2 / biosynthesis
  • DNA Primers / genetics
  • Fructokinases / antagonists & inhibitors
  • Fructokinases / genetics
  • Fructokinases / metabolism*
  • Fructose / metabolism*
  • Fructose / pharmacology
  • Humans
  • Inflammation Mediators / metabolism*
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / metabolism*
  • Male
  • Metabolic Syndrome / etiology
  • Metabolic Syndrome / metabolism
  • Oxidation-Reduction
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Renal Insufficiency, Chronic / etiology
  • Renal Insufficiency, Chronic / metabolism
  • Transfection
  • Uric Acid / pharmacology
  • Xanthine Dehydrogenase / genetics
  • Xanthine Dehydrogenase / metabolism


  • CCL2 protein, human
  • Chemokine CCL2
  • DNA Primers
  • Inflammation Mediators
  • RNA, Messenger
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Uric Acid
  • Fructose
  • Adenosine Triphosphate
  • Xanthine Dehydrogenase
  • Fructokinases
  • ketohexokinase