title: Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice.
abstract: Acute kidney injury is associated with high mortality, especially in intensive care unit patients. The polyol pathway is a metabolic route able to convert glucose into fructose. Here we show the detrimental role of endogenous fructose production by the polyol pathway and its metabolism through fructokinase in the pathogenesis of ischaemic acute kidney injury (iAKI). Consistent with elevated urinary fructose in AKI patients, mice undergoing iAKI show significant polyol pathway activation in the kidney cortex characterized by high levels of aldose reductase, sorbitol and endogenous fructose. Wild type but not fructokinase knockout animals demonstrate severe kidney injury associated with ATP depletion, elevated uric acid, oxidative stress and inflammation. Interestingly, both the renal injury and dysfunction in wild-type mice undergoing iAKI is significantly ameliorated when exposed to luteolin, a recently discovered fructokinase inhibitor. This study demonstrates a role for fructokinase and endogenous fructose as mediators of acute renal disease.
authors.affiliation: University of Colorado Denver, 12700 East 12th Ave C-281, Aurora, Colorado 80045, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Andres-Hernando
authors.affiliation: University of Colorado Denver, 12700 East 12th Ave C-281, Aurora, Colorado 80045, USA.
authors.forename: Nanxing
authors.initials: N
authors.lastname: Li
authors.affiliation: University of Colorado Denver, 12700 East 12th Ave C-281, Aurora, Colorado 80045, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Cicerchi
authors.affiliation: University of Colorado Denver, 12700 East 12th Ave C-281, Aurora, Colorado 80045, USA.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Inaba
authors.affiliation: University of Colorado Denver, 12700 East 12th Ave C-281, Aurora, Colorado 80045, USA.|Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: University of Colorado Denver, 12700 East 12th Ave C-281, Aurora, Colorado 80045, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Roncal-Jimenez
authors.affiliation: University of Colorado Denver, 12700 East 12th Ave C-281, Aurora, Colorado 80045, USA.
authors.forename: Myphuong T
authors.initials: MT
authors.lastname: Le
authors.affiliation: University of Colorado Denver, 12700 East 12th Ave C-281, Aurora, Colorado 80045, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wempe
authors.affiliation: University of Colorado Denver, 12700 East 12th Ave C-281, Aurora, Colorado 80045, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Milagres
authors.affiliation: University of Colorado Denver, 12700 East 12th Ave C-281, Aurora, Colorado 80045, USA.
authors.forename: Takuji
authors.initials: T
authors.lastname: Ishimoto
authors.affiliation: University of Colorado Denver, 12700 East 12th Ave C-281, Aurora, Colorado 80045, USA.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Fini
authors.affiliation: University of Colorado Denver, 12700 East 12th Ave C-281, Aurora, Colorado 80045, USA.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: University of Colorado Denver, 12700 East 12th Ave C-281, Aurora, Colorado 80045, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Johnson
authors.affiliation: University of Colorado Denver, 12700 East 12th Ave C-281, Aurora, Colorado 80045, USA.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Lanaspa
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D000449:Aldehyde Reductase / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D005631:Fructokinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005632:Fructose / Q000378:metabolism / Q000652:urine; D006801:Humans; D007511:Ischemia / Q000150:complications; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D047311:Luteolin / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology; D014527:Uric Acid / Q000378:metabolism
chemical_list: D020011:Protective Agents; D014527:Uric Acid; D005632:Fructose; D000449:Aldehyde Reductase; D005631:Fructokinases; C046173:fructokinase; D047311:Luteolin