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Ketohexokinase-Dependent Metabolism of Fructose Induces Proinflammatory Mediators in Proximal Tubular Cells

Pietro Cirillo^*,, Michael S. Gersch^*,, Wei Mu^*, Philip M. Scherer^*, Kyung Mee Kim, Loreto Gesualdo, George N. Henderson^*, Richard J. Johnson^* and Yuri Y. Sautin^*

Divisions of ^* Nephrology, Dialysis and Transplantation and Endocrinology and Metabolism, Department of Medicine, University of Florida, and North Florida/South Georgia Veterans Health System, Gainesville, Florida; and Division of Nephrology and Dialysis, Department of Biomedical Sciences and BioAgroMed, University of Foggia, Foggia, Italy

Correspondence: Dr. Yuri Y. Sautin, Division of Nephrology, Hypertension and Transplantation, Department of Medicine, University of Florida, P.O. Box 100224, Gainesville, FL 32610-0224. Phone: 352-273-5805; Fax: 352-392-5465; E-mail: yuri.sautin{at}medicine.ufl.edu

Received for publication June 5, 2008. Accepted for publication October 8, 2008.

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.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673