Kidney Week

Abstract: SA-PO131

Renal Phospholipid Accumulation in High-Fat Diet Fed Streptozotocin Induced Diabetic Mice Depends on Ketohexokinase

Session Information

• Diabetic Kidney Disease: Basic - III
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Doke, Tomohito, Nagoya University Graduate School of Medicine, Nagoya, Japan

Tomohito Doke,

• Ishimoto, Takuji, Nagoya University Graduate School of Medicine, Nagoya, Japan

Takuji Ishimoto,

• Hayasaki, Takahiro, Nagoya University Graduate School of Medicine, Nagoya, Japan

Takahiro Hayasaki,

• Johnson, Richard J., University of Colorado Denver , Aurora, Colorado, United States

Richard J. Johnson,

• Maruyama, Shoichi, Nagoya University Graduate School of Medicine, Nagoya, Japan

Shoichi Maruyama,

Background

Excessive fat intake contributes to the development of obesity and metabolic syndrome, which is associated with renal dysfunction in CKD patients including diabetic kidney disease (DKD). It has been reported that renal lipid metabolism may play a direct role in DKD progression. However, the detailed mechanisms of lipid metabolism in renal tubular cells of DKD remain unclear. Recently, we have reported that western diet induced steatohepatitis was dependent on ketohexokinase, a primary enzyme of fructose. Fructose is produced endogenously in DKD through the activation of polyol pathway. In this study, we investigated that the effects of fructose metabolism on lipid accumulation in DKD.

Methods

In male, C57BL6/J background wild type (WT) mice and ketohexokinase-knockout (KHK-KO) mice, which lack both KHK isoforms; KHK-A and C, diabetes was induced by streptozotocin (50mg/kg 5 consecutive days, intraperitoneal injection). They were fed 45% high fat diet (HFD) for 24 weeks, and then analyzed for renal lipid and fructose metabolism, and renal injury.

Results

Biochemical analysis demonstrated lipid parameters and blood glucose was not different between HFD fed diabetic WT and KHK-KO mice. We found remarkable vacuolization in renal proximal tubule in diabetic WT fed HFD. However, this vacuolization was prevented in diabetic KHK-KO fed HFD. This vacuolization was considered as phospholipid droplets by results of oil red o staining, toluidine blue staining and electron microscope images. The lipidomics showed renal phosphatidylglycerol (PG) was significantly increased in diabetic WT fed HFD compared to diabetic KHK-KO fed HFD. These increased renal PG was significantly correlated with phospholipid droplets, however renal triglyceride was not correlated significantly. The renal gene expressions of fatty oxidation (ACOX1, CPT1a) and cholesterol efflux (ABCA1, ABCG1, ApoE) were significantly decreased in diabetic WT fed HFD compared to diabetic KHK-KO fed HFD. These decreased gene expressions were significantly correlated with the number of phospholipid droplets.

Conclusion

These findings suggested that the inhibition of fructose metabolism in high fat fed diabetic mice ameliorated the renal phospholipid accumulation by improving the impaired fat oxidation and cholesterol efflux in kidney.