2. Academic Validation
  3. AKAPs-PKA disruptors increase AQP2 activity independently of vasopressin in a model of nephrogenic diabetes insipidus

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

  • Nat Commun. 2018 Apr 12;9(1):1411. doi: 10.1038/s41467-018-03771-2.
Fumiaki Ando 1,  Shuichi Mori 2,  Naofumi Yui 1,  Tetsuji Morimoto 3,  Naohiro Nomura 1,  Eisei Sohara 1,  Tatemitsu Rai 1,  Sei Sasaki 1,  Yoshiaki Kondo 4,  Hiroyuki Kagechika 2,  Shinichi Uchida 5
Affiliations

Affiliations

  • 1 Department of Nephrology, Tokyo Medical and Dental University (TMDU), Tokyo, 113-8510, Japan.
  • 2 Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), Tokyo, 101-0062, Japan.
  • 3 Division of Pediatrics, Tohoku Medical and Pharmaceutical University, Miyagi, 983-8512, Japan.
  • 4 Department of Health Care Services Management, Nihon University School of Medicine, Tokyo, 173-8610, Japan.
  • 5 Department of Nephrology, Tokyo Medical and Dental University (TMDU), Tokyo, 113-8510, Japan. suchida.kid@tmd.ac.jp.
PMID: 29650969 DOI: 10.1038/s41467-018-03771-2
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.

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