Abstract: TH-PO241
Endogenous Fructose Production and Fructokinase Activation Mediate Rhabdomyolysis-Induced AKI
Session Information
- AKI Basic: Cell Death and Biomarkers
November 02, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Acute Kidney Injury
- 001 AKI: Basic
Authors
- Sato, Yuka, University of Colorado Denver, Aurora, Colorado, United States
- Roncal-jimenez, Carlos Alberto, University of Colorado Denver, Aurora, Colorado, United States
- Andres-hernando, Ana, University of Colorado Denver, Aurora, Colorado, United States
- Jensen, Thomas, University of Colorado Denver, Aurora, Colorado, United States
- Kuwabara, Masanari, University of Colorado Denver, Aurora, Colorado, United States
- Johnson, Richard J., University of Colorado Denver, Aurora, Colorado, United States
- Lanaspa, Miguel A., University of Colorado Denver, Aurora, Colorado, United States
Background
Acute kidney injury (AKI) is associated with high mortality. Treatment of AKI is limited to supportive care, and no interventions to improve recovery from AKI have yet been developed. The cause of AKI is diverse including ischemia, nephrotoxic agents and rhabdomyolysis. Endogenous fructose production from glucose by the polyol pathway, and its metabolism by fructokinase (KHK) leads to ATP depletion, oxidative stress and inflammation. We have reported that the metabolism of endogenous fructose is a key deleterious step in the pathogenesis of ischemic AKI, and KHK blockade showed protective role. However, to further validate if the blockade of this pathway is clinically relevant for the treatment of other types of AKI, here, we tested the hypothesis that the endogenous fructose production and metabolism contributed to rhabdomyolysis related AKI.
Methods
To establish the rhabdomyolysis-induce AKI, male wild-type mice (WT) and KHK-deficient mice (KHK-KO) were injected with 50%v/v glycerol or saline (for control) of 6 ml/kg body weight to the two hind limbs intramuscularly. Mice were sacrificed at 24 hours after glycerol injection, and blood, urine, kidney and muscle collected for histological and biochemical analyses.
Results
Serum creatinine elevation was significantly suppressed in KHK-KO mice. (WT sham; 0.23mg/dL, KHK-KO sham; 0.10mg/dL,WT glycerol (Gly); 2.03 mg/dL, KHK-KO Gly; 1.47 mg/dL, p<0.01; WT sham vs WT Gly, p<0.01; WT Gly vs KHK-KO Gly). Serum creatine phosphokinase (CPK) levels were similar between WT and KHK-KO mice on glycerol (WT Gly; 207.5 IU/L vs KHK-KO Gly; 227.0 IU/L) suggesting equivalent muscle injury and the protective effect for rhabdomyolysis-induced AKI in KHK-KO was mediated locally at kidney. Consistently, renal endogenous fructose production and metabolism was activated in the kidney of WT Gly compared to WT sham as denoted by the up-regulation of aldose reductase and KHK.
Conclusion
Endogenous fructose production in kidney by activation of polyol pathway had a deteriorative role for rhabdomyolysis-induced AKI. The blockade of KHK could be the target for preventive and recovery for AKI.
Funding
- NIDDK Support