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

Fumiaki Ando,Shinichi Uchida,Hiroyuki Kagechika,Naofumi Yui,Tetsuji Morimoto,Shuichi Mori,Sei Sasaki,Eisei Sohara,Naohiro Nomura,Yoshiaki Kondo,Tatemitsu Rai

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.

Highlights

Congenital nephrogenic diabetes insipidus (NDI) is characterized by the inability of the kidney to concentrate urine
We report that A-kinase anchoring proteins (AKAPs)-PKA disruptors, which dissociate the binding of AKAPs and PKA R subunits, increased PKA activity and contributed to AQP2 phosphorylation, trafficking, and water reabsorption
Dissociation of AKAP binding to the PKA R subunits was found to contribute to activation of PKA and AQP2

Summary

Introduction

Congenital nephrogenic diabetes insipidus (NDI) is characterized by the inability of the kidney to concentrate urine. Circulating vasopressin increases water permeability of the collecting ducts by rapid translocation of AQP2 to the apical membranes, thereby inducing free water reabsorption from urine to the hypertonic interstitium to prevent further water loss. In this process, vasopressin binds to V2R, thereby activating adenylcyclase, which increases intracellular cyclic adenosine monophosphate (cAMP) production. G protein-coupled receptors (GPCRs), which increase cAMP production in response to their ligands, have been intensively studied[13,14,15,16,17] These conventional therapeutic approaches have failed to sufficiently activate AQP2 to increase urine osmolality and no specific pharmacological drugs have yet reached clinical application. AKAPs-PKA disruptors are potential novel category of therapeutic drugs for congenital NDI and other PKA-related diseases

Methods

Results

Conclusion