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AKAPs-PKA disruptors increase AQP2 activity independently of vasopressin in a model of nephrogenic diabetes insipidus

Author

Listed:
  • Fumiaki Ando

    (Tokyo Medical and Dental University (TMDU))

  • Shuichi Mori

    (Tokyo Medical and Dental University (TMDU))

  • Naofumi Yui

    (Tokyo Medical and Dental University (TMDU))

  • Tetsuji Morimoto

    (Tohoku Medical and Pharmaceutical University)

  • Naohiro Nomura

    (Tokyo Medical and Dental University (TMDU))

  • Eisei Sohara

    (Tokyo Medical and Dental University (TMDU))

  • Tatemitsu Rai

    (Tokyo Medical and Dental University (TMDU))

  • Sei Sasaki

    (Tokyo Medical and Dental University (TMDU))

  • Yoshiaki Kondo

    (Nihon University School of Medicine)

  • Hiroyuki Kagechika

    (Tokyo Medical and Dental University (TMDU))

  • Shinichi Uchida

    (Tokyo Medical and Dental University (TMDU))

Abstract

Congenital nephrogenic diabetes insipidus (NDI) is characterized by the inability of the kidney to concentrate urine. Congenital NDI is mainly caused by loss-of-function mutations in the vasopressin type 2 receptor (V2R), leading to impaired aquaporin-2 (AQP2) water channel activity. So far, treatment options of congenital NDI either by rescuing mutant V2R with chemical chaperones or by elevating cyclic adenosine monophosphate (cAMP) levels have failed to yield effective therapies. Here we show that inhibition of A-kinase anchoring proteins (AKAPs) binding to PKA increases PKA activity and activates AQP2 channels in cortical collecting duct cells. In vivo, the low molecular weight compound 3,3′-diamino-4,4′-dihydroxydiphenylmethane (FMP-API-1) and its derivatives increase AQP2 activity to the same extent as vasopressin, and increase urine osmolality in the context of V2R inhibition. We therefore suggest that FMP-API-1 may constitute a promising lead compound for the treatment of congenital NDI caused by V2R mutations.

Suggested Citation

  • Fumiaki Ando & Shuichi Mori & Naofumi Yui & Tetsuji Morimoto & Naohiro Nomura & Eisei Sohara & Tatemitsu Rai & Sei Sasaki & Yoshiaki Kondo & Hiroyuki Kagechika & Shinichi Uchida, 2018. "AKAPs-PKA disruptors increase AQP2 activity independently of vasopressin in a model of nephrogenic diabetes insipidus," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03771-2
    DOI: 10.1038/s41467-018-03771-2
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