Ketohexokinase-Dependent Metabolism of Fructose Induces Proinflammatory Mediators in Proximal Tubular Cells
Open Access
- 1 March 2009
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American Society of Nephrology
- Vol. 20 (3), 545-553
- https://doi.org/10.1681/asn.2008060576
Abstract
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.This publication has 50 references indexed in Scilit:
- Effect of elevated serum uric acid on cisplatin-induced acute renal failureAmerican Journal of Physiology-Renal Physiology, 2007
- CD40L Proinflammatory and Profibrotic Effects on Proximal Tubular Epithelial CellsJournal of the American Society of Nephrology, 2006
- Involvement of oxidative stress and NADPH oxidase activation in the development of cardiovascular complications in a model of insulin resistance, the fructose-fed ratAtherosclerosis, 2005
- Insulin Resistance and HypertensionHypertension, 2004
- Prevalence of the Metabolic Syndrome and Its Relation to All-Cause and Cardiovascular Mortality in Nondiabetic European Men and WomenArchives of Internal Medicine, 2004
- Uric Acid Stimulates Monocyte Chemoattractant Protein-1 Production in Vascular Smooth Muscle Cells Via Mitogen-Activated Protein Kinase and Cyclooxygenase-2Hypertension, 2003
- Presence of fructose transporter GLUT5 in the S3 proximal tubules in the rat kidneyKidney International, 1999
- HK-2: An immortalized proximal tubule epithelial cell line from normal adult human kidneyKidney International, 1994
- Fructose-induced insulin resistance and hypertension in rats.Hypertension, 1987
- Depletion of Liver Adenosine Phosphates and Metabolic Effects of Intravenous Infusion of Fructose or Sorbitol in Man and in the Rat*,**European Journal of Clinical Investigation, 1973