Kidney Week

Abstract: SA-PO110

Protein O-GlcNAcylation Regulates Renal Lipolysis During Fasting and Diabetes

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

• Sugahara, Sho, Shiga University of Medical Science, Otsu, SHIGA, Japan

Sho Sugahara,

• Kume, Shinji, Shiga University of Medical Science, Otsu, SHIGA, Japan

Shinji Kume,

• Yamahara, Kosuke, Shiga University of Medical Science, Otsu, SHIGA, Japan

Kosuke Yamahara,

• Yamahara, Mako, Shiga University of Medical Science, Otsu, SHIGA, Japan

Mako Yamahara,

• Takeda, Naoko, Shiga University of Medical Science, Otsu, SHIGA, Japan

Naoko Takeda,

• Osawa, Norihisa, Shiga University of Medical Science, Otsu, SHIGA, Japan

Norihisa Osawa,

• Kanasaki, Masami, Shiga University of Medical Science, Otsu, SHIGA, Japan

Masami Kanasaki,

• Yanagita, Motoko, Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

Motoko Yanagita,

• Araki, Shin-ichi, Shiga University of Medical Science, Otsu, SHIGA, Japan

Shin-ichi Araki,

• Maegawa, Hiroshi, Shiga University of Medical Science, Otsu, SHIGA, Japan

Hiroshi Maegawa,

Background

Energy metabolism in kidney proximal tubular cells (PTCs) is unique because their ATP production largely depends on lipolysis rather than glycolysis, regardless of feeding or fasting. Furthermore, disrupted renal lipolysis is involved in the pathogenesis of tubular damage in various kidney diseases including diabetic kidney disease. Thus, elucidating detailed mechanisms of renal fatty acid metabolism should contribute to a novel therapy for kidney diseases. O-GlcNAcylation is a post-translational modification and acts an intracellular nutrient sensor. This study was designed to examine the role of O-GlcNAcylation in renal fatty acid metabolism under fasting and diabetes.

Methods

O-GlcNAc transferase (Ogt) is the sole enzyme for O-GlcNAcylation.We generated inducible PTC-specific Ogt-knockout mice (PTC-Ogt^y/-mice) by crossbreeding female Ogt^f/fmice with male tamoxifen-inducible PTC-specific Cre transgenic mice (NDRG1-CreER^T2mice), and analyzed their renal phenotype under fasting and high fat diet (HFD)-induced obese diabetes.

Results

PTC-Ogt^y/-mice showed no significant renal phenotype under ad-libitum feeding condition, but showed significant increases in urinary excretions of albumin, glucose and various ions after 48 hours fasting. Cellular apoptosis, significant intracellular lipid droplet accumulation, mitochondrial fragmentation and decreased ATP contents in renal cortex were observed in PTCs of fasted PTC-Ogt^y/-mice. Furthermore, PTC-Ogt^y/-mice developed severe tubular cell damage under HFD-induced obesity diabetic condition. Proteomic analysis revealed that PTC-Ogt^y/-mice showed significant change in lipid metabolism pathway and dramatic decrease in protein expression level of a neutral lipid esterase, Carboxilesterase-1 (CES-1), which was associated with decreased activity in Farnesoid X receptor (FXR).

Conclusion

Protein O-GlcNAcylation is essential for maintaining renal lipolysis under fasting and obesity diabetic condition through regulating FXR-CES1 axis.