Kidney Week

Abstract: TH-PO501

AKAPs-PKA Disruptors Robustly Increase AQP2 Activity Independently of Vasopressin

Session Information

• Fluid and Electrolytes: Basic - I
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid and Electrolytes

• 901 Fluid and Electrolytes: Basic

Authors

• Ando, Fumiaki, Tokyo Medical and Dental University, Tokyo, Japan

Fumiaki Ando,

• Yui, Naofumi, Tokyo Medical and Dental University, Tokyo, Japan

Naofumi Yui,

• Nomura, Naohiro, Tokyo Medical and Dental University, Tokyo, Japan

Naohiro Nomura,

• Rai, Tatemitsu, Tokyo Medical & Dental Univ, Tokyo, Japan

Tatemitsu Rai,

• Sasaki, Sei, Tokyo Medical and Dental University, Tokyo, Japan

Sei Sasaki,

• Uchida, Shinichi, Tokyo Medical and Dental University, Tokyo, Japan

Shinichi Uchida,

Background

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. In this study, we focused on direct activators of PKA as novel therapeutic targets of congenital NDI. The intracellular distribution and activity of PKA are largely controlled by A-kinase anchoring proteins (AKAPs). We examined the effects of AKAPs-PKA disruptors, which dissociate the binding of AKAPs and PKA.

Methods

The effects of AKAPs-PKA disruptors, FMP-API-1 and its derivatives, were examined by mouse cortical collecting duct (mpkCCD) cell lines, isolated tubule microperfusion experiments, and V2R-inhibited NDI mouse model.

Results

FMP-API-1 increased PKA/AQP2 activity in mpkCCD cells. In microperfusion experiments, FMP-API-1 increased osmotic water permeability to the same extent as vasopressin. We then synthesized derivatives of FMP-API-1 to obtain greater pharmacological potency. In vivo, FMP-API-1/27 phosphorylated AQP2 at S256 and S269 more strongly than vasopressin and increased urine osmolality in V2R-inhibited NDI mouse model.

Conclusion

FMP-API-1 is a promising lead compound for the treatment of congenital NDI caused by V2R mutations.