A Role of Intestinal Alkaline Phosphatase 3 (Akp3) in Inorganic Phosphate Homeostasis

Abstract

Background/Aims: Hyperphosphatemia is a serious complication of late-stage chronic kidney disease (CKD). Intestinal inorganic phosphate (Pi) handling plays an important role in Pi homeostasis in CKD. 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 investigated Pi homeostasis in Akp3 knockout mice (Akp3^-/-). We also studied the progression of renal failure in an Akp3^-/- mouse adenine treated renal failure model. Plasma, fecal, and urinary Pi and Ca concentration were measured with commercially available kit, and plasma fibroblast growth factor 23, parathyroid hormone, and 1,25(OH)₂D₃ concentration were measured with ELISA. Brush border membrane vesicles were prepared from mouse intestine using the Ca²⁺ precipitation method and used for Pi transport activity and alkaline phosphatase activity. In vivo intestinal Pi absorption was measured with oral ³²P administration. Results: Akp3^-/- mice exhibited reduced intestinal type II sodium-dependent Pi transporter (Npt2b) protein levels and Na-dependent Pi co-transport activity. In addition, plasma active vitamin D levels were significantly increased in Akp3^-/- mice compared with wild-type animals. In the adenine-induced renal failure model, Akp3 gene deletion suppressed hyperphosphatemia. Conclusion: The present findings indicate that intestinal Akp3 deletion affects Na⁺-dependent Pi transport in the small intestine. In the adenine-induced renal failure model, Akp3 is predicted to be a factor contributing to suppression of the plasma Pi concentration.

Tissue alkaline phosphatase activity and expression in an experimental infant swine model of cardiopulmonary bypass with deep hypothermic circulatory arrest

“…Recent studies of AP in the intestines point towards a protective role against LPS and other microbacterial products, consistent with their brush border localization [ 16 , 59 , 61 , 62 ]. AP may also have a role in absorption of nutrients from the intestinal lumen [ 16 , 59 , 61 , 63 , 64 ]. The biologic role of epithelial AP in healthy kidneys is less clear [ 65 ].…”

Tissue alkaline phosphatase activity and expression in an experimental infant swine model of cardiopulmonary bypass with deep hypothermic circulatory arrest

“…[16,60,62,63] AP may also have a role in absorption of nutrients from the intestinal lumen. [16,60,62,64,65] The biologic role of epithelial AP in healthy kidneys is less clear. [66] TNAP is the predominant isoform and is located in the S1, S2, and S3 segments of the proximal tubule with a small amount of iAP present in the S3 segment as well.…”

“…[66] TNAP is the predominant isoform and is located in the S1, S2, and S3 segments of the proximal tubule with a small amount of iAP present in the S3 segment as well. [66][67][68] Preclinical data suggest that AP contributes to maintenance of inorganic phosphate homeostasis [64] and may lead to adenosine production and regulation of renovascular tone. [69] Intestinal AP activity and expression following CPB/DHCA: In this study, we found that exposure to CPB/DHCA resulted in increased ileal expression of iAP mRNA with a similar trend in the colon.…”

Tissue alkaline phosphatase activity and expression in an experimental infant swine model of cardiopulmonary bypass with deep hypothermic circulatory arrest

“…[16,55,57,58] AP may also have a role in absorption of nutrients from the intestinal lumen. [16,55,57,59,60] The biologic role of epithelial AP in healthy kidneys is less clear.…”

“…[44, 61,62] Preclinical data suggest that AP contributes to maintenance of inorganic phosphate homeostasis [59] and may lead to adenosine production and regulation of renovascular tone. [63] Intestinal AP activity and expression following CPB/DHCA: In this study, we found that exposure to the complex ischemia-reperfusion injury induced by CPB/DHCA resulted in increased ileal expression of iAP mRNA with a similar trend in the colon.…”