Japanese

Title	慢性腎臓病と糖尿病性腎臓病の治療
Subtitle	特集 マイクロバイオーム創薬研究とその将来展望
Authors	阿部高明1,2,3
Authors (kana)
Organization	東北大学 1医工学研究科, 2医学系研究科, 3AMED ムーンショットプログラム
Journal	日本薬理学雑誌
Volume	158
Number	4
Page	319-325
Year/Month	2023 / 7
Article	報告
Publisher	日本薬理学会
Abstract	腎不全に至る主要原疾患である糖尿病性腎臓病(DKD)への介入が重要視されているが, どの糖尿病患者がDKDを発症しあるいは進行してゆくかを占う指標として, eGFRや尿中アルブミンだけは不十分であり新たな指標が求められている. 糖尿病患者の体内や腸管内では様々な代謝物が合成されその病態に影響している. 我々はDKDのマーカーかつ原因候補代謝物としてフェニル硫酸(PS)を同定した. 食事中のチロシンは腸内細菌によってフェノールに変換され, 肝臓で硫酸抱合されることでPSとなり, 尿中に排泄される. 従って腎不全患者ではPSの血中濃度は高い. しかしPSは腎機能が正常でも糖尿病下ではその産生が増加しており, ポドサイト障害を惹起してアルブミン尿を増加させる. 糖尿病患者コホート(U-CARE, n=362)の解析からPSはアルブミン尿と相関し, 特に微量アルブミン群患者において2年後のアルブミン尿増悪と相関していた. さらにフェノールを産生する腸内細菌の酵素を阻害すると, 蛋白尿の減少と腎機能の改善が認められた. PSは100%腸内細菌が作るフェノールからできる代謝物であり各種腸内環境の介入によるPSの血中濃度の低下はDKDの新規かつより安全な治療法である可能性が示唆された.
Practice	薬学
Keywords	慢性腎臓病, 糖尿病性腎症, 腸内細菌, フェノール, フェニル硫酸, チロシン

English

Title	Therapy for CKD and DKD
Subtitle	Reviews : Drug Discovery Research on Microbiome and Its Future Outlook
Authors	Takaaki Abe1,2,3
Authors (kana)
Organization	1Division of Medical Science, Tohoku University Graduate School of Biomedical Engineering, 2Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, 3AMED Moon Program Manager
Journal	Folia Pharmacologica Japonica
Volume	158
Number	4
Page	319-325
Year/Month	2023 / 7
Article	Report
Publisher	The Japanese Pharmacological Society
Abstract	[Abstract.] Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Specific remedies are needed for preventing Type 2 diabetes which causes significant changes in an array of plasma metabolites. By untargeted metabolome analysis, phenyl sulfate (PS) increased with the progression of diabetes. In experimental diabetes models, PS administration induces albuminuria and podocyte damage due to the mitochondrial dysfunction. By clinical diabetic kidney disease (DKD) cohort analysis, it was also confirmed that the PS levels significantly correlate with basal and predicted 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. Inhibition of TPL reduces not only the circulating PS level but also albuminuria in diabetic mice. TPL inhibitor did not significantly alter the major composition, showing the non-lethal inhibition of microbial-specific enzymes has a therapeutic advantage, with lower selective pressure for the development of drug resistance. Clinically, 362 patients in a multi-center clinical study in diabetic nephropathy cohort (U-CARE) were analyzed with full data. The basal plasma PS level significantly correlated with ACR, eGFR, age, duration, HbA1c and uric acid, but not with suPAR. Multiple regression analysis revealed that ACR was the only factor that significantly correlated with PS. By stratified logistic regression analysis, in the microalbuminuria group, PS was the only factor related to the amount of change in the 2-year ACR in all models. PS is not only an early diagnosis marker, but also a modifiable cause and therefore a target for the treatment of DKD. Reduction of microbiota-derived phenol by the inhibitor should represent another aspect for developing drugs of DKD prevention.
Practice	Pharmaceutical sciences
Keywords

• 全文ダウンロード： 従量制、基本料金制の方共に770円(税込) です。

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