Kidney Week

Abstract: TH-OR060

Gut Microbiome-Derived Phenyl Sulfate Contributes to Albuminuria in Diabetic Kidney Disease (Part 1)

Session Information

• Diabetic Kidney Disease: Discovery of Molecular Mechanisms
  November 07, 2019 | Location: 207, Walter E. Washington Convention Center
  Abstract Time: 04:54 PM - 05:06 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Kikuchi, Koichi, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi, Japan

Koichi Kikuchi, MD

• Saigusa, Daisuke, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan

Daisuke Saigusa,

• Kanemitsu, Yoshitomi, Tohoku university Graduate school of Pharmaceutical Sciencies, Niigata, Japan

Yoshitomi Kanemitsu,

• Matsumoto, Yotaro, Tohoku university Graduate school of Pharmaceutical Sciencies, Niigata, Japan

Yotaro Matsumoto,

• Mishima, Eikan, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi, Japan

Eikan Mishima,

• Toyohara, Takafumi, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi, Japan

Takafumi Toyohara,

• Suzuki, Takehiro, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi, Japan

Takehiro Suzuki,

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

Shizuko Nagao,

• Fukuda, Shinji, Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan

Shinji Fukuda,

• Soga, Tomoyoshi, Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan

Tomoyoshi Soga,

• Tomioka, Yoshihisa, Tohoku university Graduate school of Pharmaceutical Sciencies, Niigata, Japan

Yoshihisa Tomioka,

• Abe, Takaaki, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi, Japan

Takaaki Abe,

Background

Diabetic kidney disease (DKD) is a major cause of renal failure in urgent of breakthrough in disease management. Type 2 diabetes causes significant changes in an array of plasma metabolites, and in humans, SLCO4C1 is the only transporter contributes to transport into urine. We generated transgenic (Tg) rats overexpressing SLCO4C1 in the proximal tubule, a typical human renal excretion model. Using this model, we characterize metabolites increased in diabetic wild type, but reduced in diabetic Tg rats.

Methods

Diabetes was induced by STZ. Untargeted metabolomics was performed by UHPLC-QTOF/MS . Phenyl sulfate (PS) and other uremic toxins were measured by LC/MS/MS. Mitochondrial function was analysis by Flux analyzer. The fecal 16S rRNA were analyzed by MiSeq.

Results

PS was increase with the progression of diabetes and was decreased in Tg rats with limited proteinuria. In diabetic mouse models, PS administration induced albuminuria and podocyte damage due to mitochondrial damage. By DKD cohort analysis, the PS level is correlated with basal and 2-year progression of albuminuria. Phenol is synthesized from dietary tyrosine by gut bacterial-specific tyrosine phenol-lyase (TPL) and absorbed phenol is metabolized into PS in the liver. Administration of TPL inhibitor reduced not only circulating PS level but also albuminuria in diabetic mice. Furthermore, TPL inhibitor ameliorated renal dysfunction in adenine-induced renal failure model.
Because TPL inhibitor did not alter the major composition, the non-lethal inhibition of microbial-specific enzymes has a therapeutic advantage for the development of drug resistance.

Conclusion

PS is a modifiable cause and a target for the treatment of DKD. Chemical reduction of TPL should represent another aspect for developing drugs preventing DKD (Nat. Commun. 10: 1835, 2019).