title: Fructokinase activity mediates dehydration-induced renal injury.
abstract: The epidemic of chronic kidney disease in Nicaragua (Mesoamerican nephropathy) has been linked with recurrent dehydration. Here we tested whether recurrent dehydration may cause renal injury by activation of the polyol pathway, resulting in the generation of endogenous fructose in the kidney that might subsequently induce renal injury via metabolism by fructokinase. Wild-type and fructokinase-deficient mice were subjected to recurrent heat-induced dehydration. One group of each genotype was provided water throughout the day and the other group was hydrated at night, after the dehydration. Both groups received the same total hydration in 24 h. Wild-type mice that received delayed hydration developed renal injury, with elevated serum creatinine, increased urinary NGAL, proximal tubular injury, and renal inflammation and fibrosis. This was associated with activation of the polyol pathway, with increased renal cortical sorbitol and fructose levels. Fructokinase-knockout mice with delayed hydration were protected from renal injury. Thus, recurrent dehydration can induce renal injury via a fructokinase-dependent mechanism, likely from the generation of endogenous fructose via the polyol pathway. Access to sufficient water during the dehydration period can protect mice from developing renal injury. These studies provide a potential mechanism for Mesoamerican nephropathy.
authors: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado, USA.
authors: Carlos A
authors: CA
authors: Roncal Jimenez
authors: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado, USA.
authors: Takuji
authors: T
authors: Ishimoto
authors: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado, USA.
authors: Miguel A
authors: MA
authors: Lanaspa
authors: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado, USA.
authors: Christopher J
authors: CJ
authors: Rivard
authors: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado, USA.
authors: Takahiko
authors: T
authors: Nakagawa
authors: Division of Nephrology, University of Florida, Gainesville, Florida, USA.
authors: A Ahsan
authors: AA
authors: Ejaz
authors: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado, USA.
authors: Christina
authors: C
authors: Cicerchi
authors: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado, USA.
authors: Shinichiro
authors: S
authors: Inaba
authors: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado, USA.
authors: MyPhuong
authors: M
authors: Le
authors: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado, USA.
authors: Makoto
authors: M
authors: Miyazaki
authors: La Isla Foundation, León, Nicaragua.
authors: Jason
authors: J
authors: Glaser
authors: Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
authors: Ricardo
authors: R
authors: Correa-Rotter
authors: Research Centre on Health, Work and Environment (CISTA), National Autonomous University of Nicaragua at León, (UNAN-León), León, Nicaragua.
authors: Marvin A
authors: MA
authors: González
authors: Research Centre on Health, Work and Environment (CISTA), National Autonomous University of Nicaragua at León, (UNAN-León), León, Nicaragua.
authors: Aurora
authors: A
authors: Aragón
authors: Program Work, Health and Environment in Central America, Universidad Nacional, Heredia, Costa Rica.
authors: Catharina
authors: C
authors: Wesseling
authors: Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico.
authors: Laura G
authors: LG
authors: Sánchez-Lozada
authors: 1] Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado, USA [2] Division of Nephrology, Eastern Colorado Health Care System, Department of Veteran Affairs, Denver, Colorado, USA.
authors: Richard J
authors: RJ
authors: Johnson
mesh_terms: D000449:Aldehyde Reductase / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D003681:Dehydration / Q000150:complications / Q000201:enzymology*; D004195:Disease Models, Animal; D005631:Fructokinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology; D007672:Kidney Cortex / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051436:Renal Insufficiency, Chronic / Q000201:enzymology / Q000209:etiology; D014527:Uric Acid / Q000378:metabolism
chemical_list: D014527:Uric Acid; D000449:Aldehyde Reductase; D005631:Fructokinases; C021475:ketohexokinase