The application of AKAPs-PKA disruptors to the treatment of nephrogenic diabetes insipidus

2018 Fiscal Year Final Research Report

• Project/Area Number: 17H06656
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Kidney internal medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Ando Fumiaki 東京医科歯科大学, 医学部附属病院, 特任助教 (80804559)
• Research Collaborator: MORI shuichi
• Project Period (FY): 2017-08-25 – 2019-03-31
• Keywords: 先天性腎性尿崩症 / AKAPs / PKA / AQP2水チャネル / AKAPs-PKA結合阻害剤

Outline of Final Research Achievements

Congenital nephrogenic diabetes insipidus (NDI) is characterized by defective urine concentrating ability. Congenital NDI is mainly caused by loss-of-function mutations in the vasopressin type 2 receptor (V2R), leading to inactivation of cAMP/PKA/AQP2 water channels signaling pathway. We focused on direct activators of PKA as novel therapeutic targets of congenital NDI. The intracellular distribution and substrate specificity of PKA are largely controlled by A-kinase anchoring proteins (AKAPs). Low molecular weight compounds that inhibit AKAPs binding to PKA significantly increased PKA activity in renal collecting ducts and activated AQP2 to the same extent as vasopressin.

Free Research Field

腎臓

Academic Significance and Societal Importance of the Research Achievements

昼夜を問わない多尿と脱水症の回避に必要な多量の飲水は、先天性腎性尿崩症患者のQOLを著しく低下させ、社会活動の制限を招く。さらに、多尿は精神発達遅滞や腎機能低下などの重篤な合併症を引き起こす危険性があり、根治的治療法の開発が望まれている。最近では、加齢・薬剤などによる後天性の尿濃縮障害も、脱水・熱中症を引き起こすため解決すべき問題となっている。AKAPs-PKA結合阻害剤によるPKAの直接活性化は新規尿濃縮力改善薬の標的として有望である。