Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice

Ana Andres-Hernando,Christina Cicerchi,Wei Chen,Shinichiro Inaba,Takahiko Nakagawa,Tamara Milagres,Carlos Roncal-Jimenez,Richard J Johnson,Myphuong T Le,Takuji Ishimoto,Mehdi Fini,Nanxing Li,Miguel A Lanaspa,Michael F Wempe

doi:10.1038/ncomms14181

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.

Highlights

Acute kidney injury is associated with high mortality, especially in intensive care unit patients
Activation of the polyol pathway in human patients with Acute kidney injury (AKI) might be reflected by a significant increase in urinary fructose levels associated with significant tubular injury
To determine the specific deleterious role of endogenous fructose production after aldose reductase activation and its metabolism though fructokinase, we evaluated the effect of radiocontrast agents in diabetic wild type and fructokinasedeficient mice as previously described elsewhere[35,36]

Summary

Introduction

Acute kidney injury is associated with high mortality, especially in intensive care unit patients. 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. Blockade of fructokinase expression in renal proximal tubular cells inhibits fructose-induced production of oxidative stress and cell injury[20] In this manuscript, we test the novel hypothesis that endogenous fructose production generated by the polyol pathway is a deleterious mechanism for causing ischaemic AKI (iAKI). The blockade of this pathway could be clinically relevant as means to prevent iAKI (such as in cardiovascular surgery) and as a target to accelerate renal recovery after the onset of renal injury

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Results

Conclusion