Kidney Week

Abstract: TH-PO684

Glucose Metabolic Profiles in Renal Tissue of an Orthologous PCK Rat Model of Human PKD Using Metabolic and Proteomic Analyses

Session Information

• ADPKD: Genetic and Model Studies
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidney

• 1001 Genetic Diseases of the Kidney: Cystic

Authors

• Nagao, Shizuko, Fujita Health University, Toyoake, Aichi, Japan

Shizuko Nagao,

• Kugita, Masanori, Fujita Health University, Toyoake, Aichi, Japan

Masanori Kugita,

• Kumamoto, Kanako, Fujita Health University, Toyoake, Aichi, Japan

Kanako Kumamoto,

• Yoshimura, Aya, Fujita Health University, Toyoake, Aichi, Japan

Aya Yoshimura,

• Yamaguchi, Tamio, Suzuka University of Medical Science, Suzuka, Mie, Japan

Tamio Yamaguchi,

• Nakajima, Kazuki, Fujita Health University, Toyoake, Japan

Kazuki Nakajima,

• Takahashi, Kazuo, Fujita Health University School of Medicine, Toyoake, AICHI-KEN, Japan

Kazuo Takahashi,

• Yuzawa, Yukio, Fujita Health University School of Medicine, Toyoake, AICHI-KEN, Japan

Yukio Yuzawa,

Background

Polycystic kidney disease (PKD) is an inherited disorder characterized by excessive cellular proliferation and fluid secretion of the tubular epithelial cells due to genetic mutation. To detect altered renal metabolic and enzymatic activities, we performed metabolic and proteomic analyses in the PCK rat, an orthologous model of human autosomal recessive PKD.

Methods

In renal tissue of 20-week-old PCK and age-matched normal rats, metabolic products were analyzed by using capillary electrophoresis time-of-flight mass spectrometry and MasterHands metabolome analysis software; proteomic products were analyzed using Orbitrap mass spectrometry and Proteome Discoverer™ software.

Results

Metabolic analysis revealed a 1.8-fold increase in cAMP content in PCK cystic kidneys compared with normal kidneys, the same trend seen from our previous study using radioimmunoassay. Upstream glycolysis metabolites were decreased as follows: glucose 1-phosphate (0.5-fold), glucose 6-phosphate (0.5-fold) and fructose 6-phosphate (F6P, 0.6-fold); and downstream, 3-phosphoglyceric acid (3-PG, 4.2-fold) was increased in PCK samples. 2-Phosphoglyceric acid and phosphoenolpyruvate were detected in only PCK kidneys, not in normal kidneys. On proteomic analysis, increased fructose-bisphosphate aldolase A, an enzyme that converts F6P to 3-PG, was seen in PCK rats (3.6-fold). Tricarboxylic acid (TCA) cycle metabolites were increased as follows: citric acid (23-fold), cis-aconitic acid (8.5-fold), isocitric acid (32-fold), succinic acid (1.6-fold), fumaric acid (1.7-fold), and malic acid (2.1-fold) in PCK kidneys; 2-oxoglutarate was detected in only PCK kidneys. Citrate synthase, which converts acetyl CoA (2.0-fold) to citric acid, was increased (7.5-fold) in PCK kidneys. In the non-oxidative phase of the pentose phosphate pathway, increased ribose 5-phosphate (R5P) was detected in only PCK kidneys. Increased transaldolase (3.0-fold), which converts sedoheptulose 7-phosphate (S7P, 0.6-fold) to F6P, was found in PCK kidneys. Also, transketolase (2.4-fold), which converts S7P to R5P, was increased in PCK cystic kidneys.

Conclusion

These findings suggest that increased activity of pentose phosphate pathway as well as glycolysis and TCA cycle may play important roles in promoting PKD progression.

Funding

• Government Support - Non-U.S.