title: Aging-associated renal disease in mice is fructokinase dependent.
abstract: Aging-associated kidney disease is usually considered a degenerative process associated with aging. Recently, it has been shown that animals can produce fructose endogenously, and that this can be a mechanism for causing kidney damage in diabetic nephropathy and in association with recurrent dehydration. We therefore hypothesized that low-level metabolism of endogenous fructose might play a role in aging-associated kidney disease. Wild-type and fructokinase knockout mice were fed a normal diet for 2 yr that had minimal (<5%) fructose content. At the end of 2 yr, wild-type mice showed elevations in systolic blood pressure, mild albuminuria, and glomerular changes with mesangial matrix expansion, variable mesangiolysis, and segmental thrombi. The renal injury was amplified by provision of high-salt diet for 3 wk, as noted by the presence of glomerular hypertrophy, mesangial matrix expansion, and alpha smooth muscle actin expression, and with segmental thrombi. Fructokinase knockout mice were protected from renal injury both at baseline and after high salt intake (3 wk) compared with wild-type mice. This was associated with higher levels of active (phosphorylated serine 1177) endothelial nitric oxide synthase in their kidneys. These studies suggest that aging-associated renal disease might be due to activation of specific metabolic pathways that could theoretically be targeted therapeutically, and raise the hypothesis that aging-associated renal injury may represent a disease process as opposed to normal age-related degeneration.
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado; carlos.roncal@ucdenver.edu.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Roncal-Jimenez
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado; Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Ishimoto
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Lanaspa
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado.
authors.forename: Tamara
authors.initials: T
authors.lastname: Milagres
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado.
authors.forename: Ana Andres
authors.initials: AA
authors.lastname: Hernando
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jensen
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado.
authors.forename: Makoto
authors.initials: M
authors.lastname: Miyazaki
authors.affiliation: Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tomohito
authors.initials: T
authors.lastname: Doke
authors.affiliation: Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Hayasaki
authors.affiliation: TMK Project, Medical Innovation Center, Kyoto University, Kyoto, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Marumaya
authors.affiliation: Developmental Biology and Cancer Programme, UCL Institute of Child Health, London, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Long
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado.
authors.forename: Gabriela E
authors.initials: GE
authors.lastname: Garcia
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado.
authors.forename: Masanari
authors.initials: M
authors.lastname: Kuwabara
authors.affiliation: Laboratory of Renal Physiopathology and Department of Nephrology, Instituto Nacional de Cardiologia I.Ch., Mexico City, Mexico.
authors.forename: Laura G
authors.initials: LG
authors.lastname: Sánchez-Lozada
authors.affiliation: Department of Internal Medicine, Ewha Womans University School of Medicine, Ewha Medical Research Center, Seoul, Republic of Korea; and.
authors.forename: Duk-Hee
authors.initials: DH
authors.lastname: Kang
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado; Division of Nephrology, Eastern Colorado Health Care System, Department of Veteran Affairs, Denver, Colorado.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Johnson
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000419:Albuminuria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D003404:Creatinine / Q000097:blood; D005631:Fructokinases / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000071068:Lipocalin-2 / Q000652:urine; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation
chemical_list: D000071068:Lipocalin-2; C071332:Lcn2 protein, mouse; D003404:Creatinine; D052250:Nitric Oxide Synthase Type III; D005631:Fructokinases; C046173:fructokinase
keywords: aging; chronic kidney disease; fructose