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.

Fructokinase Inhibitors–in Diabetic Nephropathy

“…Selective injury to the proximal tubule can result in glomerular damage, possibly because of connecting tubule glomerular feedback in which reflex arteriolar vasodilation from tubular damage causes increases in glomerular pressure. [16,17] ANIMAL STUDY WITH FRUCTOKINASE INHIBITOR [18] Luteolin -recently exposed as fructokinase inhibitor ameliorates renal injury. [18] Acute kidney injury is linked with high mortality, particularly in intensive care unit patients.…”

“…[16,17] ANIMAL STUDY WITH FRUCTOKINASE INHIBITOR [18] Luteolin -recently exposed as fructokinase inhibitor ameliorates renal injury. [18] Acute kidney injury is linked with high mortality, particularly in intensive care unit patients. severe kidney injury associated with ATP depletion, elevated uric acid, oxidative stress and inflammation.…”

“…Remarkably, both the renal injury and dysfunction in wild-type mice undergoing iAKI is significantly ameliorated when exposed to luteolin, a recently discovered fructokinase inhibitor. [18] Role of fructokinase in pathogenesis of DN [4] is well clear and fructokinase inhibitors can ameliorate kidney injury/damage. [18] Probable benefits of Fructokinase Inhibitors Fructokinase is novel target for DN [4] and needs further evaluation.…”

“…[18] Role of fructokinase in pathogenesis of DN [4] is well clear and fructokinase inhibitors can ameliorate kidney injury/damage. [18] Probable benefits of Fructokinase Inhibitors Fructokinase is novel target for DN [4] and needs further evaluation. [4,18] Unfortunately only one fructokinase inhibitor Luteolin is studied till date in kidney injury and diabetic nephropathy.…”

“…[18] Probable benefits of Fructokinase Inhibitors Fructokinase is novel target for DN [4] and needs further evaluation. [4,18] Unfortunately only one fructokinase inhibitor Luteolin is studied till date in kidney injury and diabetic nephropathy. Newer fructokinase inhibitor molecules should be tested in preclinical study.…”