title: Endogenous fructose production and fructokinase activation mediate renal injury in diabetic nephropathy.
abstract: Diabetes is associated with activation of the polyol pathway, in which glucose is converted to sorbitol by aldose reductase. Previous studies focused on the role of sorbitol in mediating diabetic complications. However, in the proximal tubule, sorbitol can be converted to fructose, which is then metabolized largely by fructokinase, also known as ketohexokinase, leading to ATP depletion, proinflammatory cytokine expression, and oxidative stress. We and others recently identified a potential deleterious role of dietary fructose in the generation of tubulointerstitial injury and the acceleration of CKD. In this study, we investigated the potential role of endogenous fructose production, as opposed to dietary fructose, and its metabolism through fructokinase in the development of diabetic nephropathy. Wild-type mice with streptozotocin-induced diabetes developed proteinuria, reduced GFR, and renal glomerular and proximal tubular injury. Increased renal expression of aldose reductase; elevated levels of renal sorbitol, fructose, and uric acid; and low levels of ATP confirmed activation of the fructokinase pathway. Furthermore, renal expression of inflammatory cytokines with macrophage infiltration was prominent. In contrast, diabetic fructokinase-deficient mice demonstrated significantly less proteinuria, renal dysfunction, renal injury, and inflammation. These studies identify fructokinase as a novel mediator of diabetic nephropathy and document a novel role for endogenous fructose production, or fructoneogenesis, in driving renal disease.
authors.affiliation: The Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, Colorado; Miguel.lanaspagarcia@ucdenver.edu.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Lanaspa
authors.affiliation: The Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, Colorado;
authors.forename: Takuji
authors.initials: T
authors.lastname: Ishimoto
authors.affiliation: The Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, Colorado;
authors.forename: Christina
authors.initials: C
authors.lastname: Cicerchi
authors.affiliation: The Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, Colorado;
authors.forename: Yoshifuru
authors.initials: Y
authors.lastname: Tamura
authors.affiliation: The Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, Colorado;
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Roncal-Jimenez
authors.affiliation: The Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, Colorado;
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: The Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, Colorado;
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Tanabe
authors.affiliation: The Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, Colorado;
authors.forename: Ana
authors.initials: A
authors.lastname: Andres-Hernando
authors.affiliation: The Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, Colorado;
authors.forename: David J
authors.initials: DJ
authors.lastname: Orlicky
authors.affiliation: The Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, Colorado; Venezuelan Scientific Research Institute and University Hospital of Zulia, Maracaibo, Venezuela;
authors.forename: Esteban
authors.initials: E
authors.lastname: Finol
authors.affiliation: The Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, Colorado;
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Inaba
authors.affiliation: The Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, Colorado;
authors.forename: Nanxing
authors.initials: N
authors.lastname: Li
authors.affiliation: The Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, Colorado;
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rivard
authors.affiliation: Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kosugi
authors.affiliation: The Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, Colorado; Laboratory of Renal Physiopathology and Department of Nephrology, INC Ignacio Chavez, Mexico City, Mexico;
authors.forename: Laura G
authors.initials: LG
authors.lastname: Sanchez-Lozada
authors.affiliation: The Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, Colorado;
authors.forename: J Mark
authors.initials: JM
authors.lastname: Petrash
authors.affiliation: Division of Nephrology and Hypertension, and.
authors.forename: Yuri Y
authors.initials: YY
authors.lastname: Sautin
authors.affiliation: Division of Nephrology, Hypertension, and Transplantation, University of Florida, Gainesville, Florida;
authors.forename: A Ahsan
authors.initials: AA
authors.lastname: Ejaz
authors.affiliation: The Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, Colorado;
authors.forename: Wataru
authors.initials: W
authors.lastname: Kitagawa
authors.affiliation: The Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, Colorado;
authors.forename: Gabriela E
authors.initials: GE
authors.lastname: Garcia
authors.affiliation: Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, United Kingdom; and.
authors.forename: David T
authors.initials: DT
authors.lastname: Bonthron
authors.affiliation: Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, United Kingdom; and.
authors.forename: Aruna
authors.initials: A
authors.lastname: Asipu
authors.affiliation: Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, United Kingdom; and.
authors.forename: Christine P
authors.initials: CP
authors.lastname: Diggle
authors.affiliation: Venezuelan Scientific Research Institute and University Hospital of Zulia, Maracaibo, Venezuela;
authors.forename: Bernardo
authors.initials: B
authors.lastname: Rodriguez-Iturbe
authors.affiliation: The Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, Colorado; TMK Project, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: The Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, Colorado;
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Johnson
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D002461:Cell Line, Transformed; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D005631:Fructokinases / Q000378:metabolism*; D005632:Fructose / Q000096:biosynthesis* / Q000378:metabolism*; D006801:Humans; D007672:Kidney Cortex / Q000201:enzymology / Q000473:pathology; D007678:Kidney Glomerulus / Q000166:cytology / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000201:enzymology* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011108:Polymers / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D018925:Chemokines; D016207:Cytokines; D011108:Polymers; C024617:polyol; D005632:Fructose; D005631:Fructokinases; C046173:fructokinase