Abstract: TH-PO687

Deficiency of Ketohexokinase-A Exacerbates Renal Tubular Injury in Streptozotocin-Induced Diabetic Mice

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Doke, Tomohito, Nagoya University Graduate School of Medicine, Nagoya, Japan
  • Ishimoto, Takuji, Nagoya University Graduate School of Medicine, Nagoya, Japan
  • Hayasaki, Takahiro, Nagoya University Graduate School of Medicine, Nagoya, Japan
  • Lanaspa, Miguel A., University of Colorado Denver, Aurora, Colorado, United States
  • Johnson, Richard J., University of Colorado Denver, Aurora, Colorado, United States
  • Maruyama, Shoichi, Nagoya University Graduate School of Medicine, Nagoya, Japan
Background

Ketohexokinase (KHK), a primary enzyme for fructose, exists as two isoforms, KHK-C and KHK-A. Recently, we have reported that the metabolism of fructose endogenously produced by polyol pathway activation in diabetes may have a deleterious role in the pathogenesis of diabetic nephropathy using mice lacking both KHK-A and KHK-C (KHK-A/C KO). Although both isoforms express in proximal tubule, the role of KHK-A is not yet elucidated. The aim of this study is to determine the role of KHK-A in the development of diabetic nephropathy.

Methods

Male wild-type mice (WT), KHK-A knockout mice (KHK-A KO), and KHK-A/C KO were used. Diabetes was induced with i.p. injections of streptozotocin (5 days). At 18 weeks, urine, blood, and kidney tissues were collected from diabetic (D) and control mice. Renal injuries, inflammation, hypoxia, oxidative stress, and polyol pathway enzymes were analyzed. Metabolomic analysis including polyol pathway, fructose metabolism, nucleotides, glycolysis, and TCA cycle in kidney and urine was done.

Results

The levels of blood glucose were equally elevated, and polyol pathway in kidney was similarly activated among all mice induced diabetes. However, D-WT and D-KHK-A KO showed increases of urinary NGAL, glomerular hypertrophy, and tubular injuries with increased oxidative stress and renal XO activity compared to D- KHK-A/C KO. Urinary NGAL was significantly associated with renal AMP and urinary allantoin. Moreover, those renal injuries were more severe in D-KHK-A KO accompanied by significant renal dysfunction, increases of renal inflammatory cytokines and HIF1alpha expressions. Metabolomic analysis revealed elevations of renal fructose and fructose-1-phosphate contents in D-WT and D-KHK-A KO compared with respective controls. Furthermore, downstream metabolites of fructose, renal DHAP (Dihydroxyacetone phosphate) and TCA cycle were significantly increased in D-KHK-A KO compared with D-WT and D-KHK-A/C KO.

Conclusion

Kidney injury in streptozotocin-induced diabetes was exacerbated in mice lacking KHK-A with increased endogenous fructose metabolism than WT, while that was prevented in mice lacking both isoforms. These results suggest that KHK-C has a deleterious role, and KHK-A might has an opposite role in endogenous fructose-related kidney injury in diabetic mice.