Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular cells.
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.
Cirillo
Pietro
P
Division of Nephrology, Hypertension and Transplantation, Department of Medicine, University of Florida, Gainesville, FL 32610-0224, USA.
Gersch
Michael S
MS
Mu
Wei
W
Scherer
Philip M
PM
Kim
Kyung Mee
KM
Gesualdo
Loreto
L
Henderson
George N
GN
Johnson
Richard J
RJ
Sautin
Yuri Y
YY
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D018932:Chemokine CCL2 / Q000096:biosynthesis; D017931:DNA Primers / Q000235:genetics; D005631:Fructokinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005632:Fructose / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology / Q000378:metabolism; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000209:etiology / Q000378:metabolism; D014162:Transfection; D014527:Uric Acid / Q000494:pharmacology; D014968:Xanthine Dehydrogenase / Q000235:genetics / Q000378:metabolism
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D017931:DNA Primers; D018836:Inflammation Mediators; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014527:Uric Acid; D005632:Fructose; D000255:Adenosine Triphosphate; D014968:Xanthine Dehydrogenase; D005631:Fructokinases; C021475:ketohexokinase