The clinical application of a novel biomarker and therapeutic strategy in diabetic kidney disease

• Project/Area Number: 19K23994
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0904:Internal medicine of the bio-information integration and related fields
• Research Institution: Tohoku University
• Principal Investigator: KIKUCHI Koichi 東北大学, 東北メディカル・メガバンク機構, 助教 (10845259)
• Project Period (FY): 2019-08-30 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 糖尿病性腎臓病 / 腸内細菌叢 / フェニル硫酸 / チロシンフェノールリアーゼ / 末期腎不全 / バイオマーカー / 腸腎連関 / TPL阻害剤 / 腸内細菌叢の変容 / PS産生亢進 / 腸内細菌

Outline of Research at the Start

糖尿病性腎臓病（DKD）は末期腎不全に至る最多の原疾患であり発症者の早期発見や進展予防は急務の課題であるが、既存の血糖管理や血圧管理といった治療だけでは進行を止められない症例も多い。また一般にDKDの評価に用いられるアルブミン尿やeGFRといった指標ではこれらが顕在化してからでは手遅れとなってしまう症例もある。
申請者は腸内細菌酵素によってチロシンから産生されるフェノールの代謝物であるフェニル硫酸がDKD発症の早期発見マーカーであり治療ターゲットとなり得ることを明らかにした。
本研究は腸内細菌というこれまでのDKD治療や診断マーカーにない新たな分野を対象とした研究で極めて新規性が高い研究である。

Outline of Final Research Achievements

Diabetic kidney disease (DKD) is one of the major causes of end-stage renal diseases (ESRD) in Japan, and it is very important to prevent from onset or progression of DKD.
In previous study (Kikuchi et al Nat. Med. 2019), we identified phenyl sulfate (PS) as a novel biomarker of DKD. PS is a metabolite of phenol which produced from tyrosine by tyrosine-phenol lyase (TPL). PS administration in several types of diabetic nephropathy model significantly induced albuminuria and podocyte damage, suggesting that PS may be one of the causes of albuminuria in db/db mice.In this study, we clarify that a production of PS is increased in diabetic condition according to change gut microbiota. This implied microbiota may be a therapeutic target in DKD. Next, we identified compounds which decreasing plasma PS concentration by pharmacological screening because we clarify the reduction of PS have reno-protective effect.

Academic Significance and Societal Importance of the Research Achievements

糖尿病性腎臓病は末期腎不全に至る最多原疾患であり、腎不全に至ると透析治療を余儀なくされる。末期腎不全は患者のQOLを著しく低下させるだけでなく、透析治療には患者一人あたり年間約500万円の医療費がかかっており医療経済的にも末期腎不全患者数を減らすことは極めて重要である。本研究は腸内細菌叢に着目し糖尿病性腎臓病の新たな発症予測マーカーや治療法の可能性を示したものであり、学術的・社会的意義は大である。

Research Products

• [Journal Article] Germ-free conditions modulate host purine metabolism, exacerbating adenine-induced kidney damage. (2020)
  • Author(s): Mishima E, Ishijo M, Kawabe T, Kikuchi K, Akiyama Y, Toyohara T, Suzuki C, Asao A, Ishii N, Fukuda S, Abe T
  • Journal Title: Toxins Volume: 12 Issue: 9 Pages: 547-547
  • DOI: 10.3390/toxins12090547
  • Peer Reviewed / Open Access
• [Journal Article] Kidney enlargement effect of angioplasty for nonatherosclerotic renovascular disease: reversibility of ischemic kidney (2020)
  • Author(s): Iwasaki Tomoyuki、Mishima Eikan、Suzuki Takehiro、Kikuchi Koichi、Toyohara Takafumi、Seiji Kazumasa、Takase Kei、Miyazaki Mariko、Harigae Hideo、Ito Sadayoshi、Abe Takaaki
  • Journal Title: Hypertension Research Volume: 43 Issue: 11 Pages: 1214-1221
  • DOI: 10.1038/s41440-020-0473-6
  • Peer Reviewed / Open Access
• [Journal Article] Drugs Repurposed as Antiferroptosis Agents Suppress Organ Damage, Including AKI, by Functioning as Lipid Peroxyl Radical Scavengers (2019)
  • Author(s): Mishima Eikan、Sato Emiko、Ito Junya、Yamada Ken-ichi、Suzuki Chitose、Oikawa Yoshitsugu、Matsuhashi Tetsuro、Kikuchi Koichi、Toyohara Takafumi、Suzuki Takehiro、Ito Sadayoshi、Nakagawa Kiyotaka、Abe Takaaki
  • Journal Title: Journal of the American Society of Nephrology Volume: 31 Issue: 2 Pages: 280-296
  • DOI: 10.1681/asn.2019060570
  • Peer Reviewed / Open Access
• [Journal Article] The guanylate cyclase C agonist linaclotide ameliorates the gut?cardio?renal axis in an adenine-induced mouse model of chronic kidney disease (2019)
  • Author(s): Nanto-Hara F、Kanemitsu Y、Fukuda S、Kikuchi K、Asaji K、Saigusa D、Iwasaki T、Ho H、Mishima E、Suzuki T、Suzuki C、Tsukimi T、Matsuhashi T、Oikawa Y、Akiyama Y、Kure S、Owada Y、Tomioka Y、Soga T、Ito S, Abe T
  • Journal Title: Nephrology Dialysis Transplantation Volume: 35 Pages: 250-264
  • DOI: 10.1093/ndt/gfz126
  • Peer Reviewed / Open Access
• [Presentation] The clinical importance of gut microbiome-derived phenyl sulfate as a predictive marker of albuminuria in diabetic kidney disease (2020)
  • Author(s): Koichi Kikuchi, Daisuke Saigusa, Yoshitomi Kanemitsu, Yotaro Matsumoto, Koki Mise, Tomohiro Nakamura, Atsushi Hozawa, Jun Wada, Yoshihisa Tomioka, Takaaki Abe
  • Organizer: 9th CKD frontier meeting
  • Int'l Joint Research
• [Presentation] 糖尿病性腎臓病の新規発症、進展予測マーカーとしてのフェニル硫酸の意義 (2020)
  • Author(s): 菊地晃一、三枝大輔、金光祥臣、松本洋太郎、中村智洋、三瀬広記、寶澤篤、和田淳、富岡佳久、阿部高明
  • Organizer: 第63回 日本糖尿病学会年次集会
• [Presentation] Gut microbiome-derived phenyl sulfate contributes to albuminuria in diabetic kidney disease (2020)
  • Author(s): Koichi Kikuchi, Daisuke Saigusa, Matsumoto Yotaro, Mise Koki, Tomohiro, Nakamura, Eikan Mishima, Takafumi Toyohara, Takehiro Suzuki, Atsushi Hozawa, Jun Wada, Yoshihisa Tomioka, Takaaki Abe
  • Organizer: 第80回米国糖尿病学会議
  • Int'l Joint Research
• [Presentation] 糖尿病性腎症の発症・進展予測マーカーとしてのフェニル硫酸の有用性 (2020)
  • Author(s): 菊地晃一、三枝大輔、金光祥臣、松本洋太郎、三瀬広記、中村智洋、 三島英換、豊原敬文、鈴木健弘、寳澤篤、和田淳、富岡佳久、阿部高明
  • Organizer: 第63回日本腎臓学会総会
• [Presentation] The clinical importance of gut microbiome-derived phenyl sulfate as a predictive marker of albuminuria in diabetic kidney disease (2020)
  • Author(s): 菊地晃一
  • Organizer: 9th CKD frontier meeting
  • Int'l Joint Research
• [Presentation] Gut microbiome-derived phenyl sulfate contributes to albuminuria in diabetic kidney disease (Part 1, Basic) (2019)
  • Author(s): 菊地晃一
  • Organizer: 第52回米国腎臓学会議
  • Int'l Joint Research
• [Presentation] 腸内細菌酵素由来のフェニル硫酸は糖尿病性腎臓病のアルブミン尿増悪の原因物質かつ進展予測マーカーである (2019)
  • Author(s): 菊地晃一
  • Organizer: 第31回糖尿病性腎症研究会
• [Presentation] 糖尿病性腎症の新規発症・進展予測マーカーとしてのフェニル硫酸の有用性の臨床検討 (2019)
  • Author(s): 菊地晃一
  • Organizer: 第10回腎不全研究会