Abstract: TH-OR009
Derivatives of FMP-API-1/27 Robustly Activate AQP2 Water Channels Independently of Vasopressin
Session Information
- Advances in Fluid and Electrolyte Handling: Basic Physiology
November 07, 2019 | Location: 146 C, Walter E. Washington Convention Center
Abstract Time: 06:06 PM - 06:18 PM
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
- Mandai, Shintaro, Tokyo Medical and Dental University, Tokyo, Japan
- Isobe, Kiyoshi, Tokyo Medical and Dental University, Tokyo, Japan
- Mori, Takayasu, Tokyo Medical and Dental University, Tokyo, Japan
- Susa, Koichiro, Tokyo Medical and Dental University, Tokyo, Japan
- Nomura, Naohiro, Tokyo Medical and Dental University, Tokyo, Japan
- Sohara, Eisei, Tokyo Medical and Dental University, Tokyo, Japan
- Rai, Tatemitsu, 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 channels activity in renal collecting ducts. Direct activators of protein kinase A (PKA) are novel therapeutic targets of congenital NDI. The intracellular distribution and activity of PKA are largely controlled by A-kinase anchoring proteins (AKAPs). We found that a low molecular weight compound, FMP-API-1/27, dissociated AKAPs binding to PKA and activated PKA/AQP2. We promoted further development of FMP-API-1/27 derivatives in terms of pharmaceutical potency and feasibility.
Methods
The effects of compounds on PKA/AQP2 were examined by a mouse cortical collecting duct (mpkCCD) cell line and a V2R-inhibited NDI mouse model.
Results
We examined the effects of screening compounds with similar structures to FMP-API-1/27 from TMDU Chemical Biology Database and derivatives of FMP-API-1/27 using mpkCCD cells. Hit compounds that increased PKA/AQP2 activity had similar chemical structures. We then developed compound X, which phosphorylated AQP2 at S269 to the same extent as vasopressin in mpkCCD cells. In vivo, compound Y significantly increased urine osmolality and decreased urine output in a V2R-inhibited NDI mouse model.
Conclusion
Derivatives of FMP-API-1/27 are promising therapeutic targets for congenital NDI caused by V2R mutations.