ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: TH-PO501

AKAPs-PKA Disruptors Robustly Increase AQP2 Activity Independently of Vasopressin

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Authors

  • Ando, Fumiaki, Tokyo Medical and Dental University, Tokyo, Japan
  • Yui, Naofumi, Tokyo Medical and Dental University, Tokyo, Japan
  • Nomura, Naohiro, Tokyo Medical and Dental University, Tokyo, Japan
  • Rai, Tatemitsu, Tokyo Medical & Dental Univ, Tokyo, Japan
  • Sasaki, Sei, Tokyo Medical and Dental University, Tokyo, Japan
  • Uchida, Shinichi, Tokyo Medical and Dental University, Tokyo, Japan
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.