Abstract: TH-PO540
Intestinal Environmental Control and Renal Protection by Intestinal Alkaline Phosphatase (IAP)
Session Information
- Bone and Mineral Metabolism: Basic
November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Bone and Mineral Metabolism
- 401 Bone and Mineral Metabolism: Basic
Authors
- Segawa, Hiroko, Tokushima University, Tokushima City, Japan
- Sasaki, Sumire, Tokushima University, Tokushima City, Japan
- Arima, Yuki, Tokushima University, Tokushima City, Japan
- Hanazaki, Ai, Tokushima University, Tokushima City, Japan
- Koike, Megumi, Tokushima University, Tokushima City, Japan
- Tanifuji, Kazuya, Tokushima University, Tokushima City, Japan
- Miyamoto, Ken-ichi, Tokushima University, Tokushima City, Japan
Background
Hyperphosphatemia is an independent risk factor for mortality, and prevention and correction of it is a major goal of the treatment of chronic kidney disease (CKD). Inorganic phosphate (Pi) balance is maintained by intestinal absorption, renal excretion, and bone accretion. Especially, the regulation of intestinal Pi absorption is an important target for the treatment of hyperphosphatemia.
Intestinal alkaline phosphatase (IAP) is a brush border phosphomonoesterase that catalyzes the hydrolysis of nonspecific Pi ester bonds at an alkaline pH, and a plasma membrane-bound glycoprotein that dephosphorylates several substrates, including Pi additives. The relationship between IAP and Pi metabolism is not clear. We investigated whether intestinal alkaline phosphatase 3(Akp3), the enzyme that hydrolyzes dietary Pi compounds, is a target for the treatment of hyperphosphatemia in CKD.
Methods
We analyzed Pi homeostasis in Akp3 knockout mice (Akp3-/-), and studied the progression of renal failure, and intestinal environment in an Akp3-/- renal failure model.
Results
In humans, rats, and mice, intestinal alkaline phosphatase (IAP, AKP3) is expressed throughout the gastrointestinal tract with the highest expression in the duodenum. Akp3-/- mice have high luminal ATP concentrations, which affects bacterial growth in the gut. Changes in the extracellular ATP concentration affected Pi transport. In the renal failure model, genetic deletion of Akp3 suppressed abnormal mineral homeostasis, progression of renal failure and inflammation of the intestinal and whole body in Akp3+/+. As a result, Akp3-/- extended the life span compared to Akp3+/+. In the Akp3-/- renal failure model, hyperphosphatemia was alleviated by suppression of intestinal Pi absorption via paracellular mechanisms as well as transcellular Pi transport.
Conclusion
Elucidation of the mechanism of suppression of renal disease progression confirmed by Akp3-/- could contribute to the development of a new CKD treatment.
Funding
- Government Support - Non-U.S.