Tmem174, a regulator of phosphate transporter prevents hyperphosphatemia

Abstract

Renal type II sodium-dependent inorganic phosphate (Pi) transporters NaPi2a and NaPi2c cooperate with other organs to strictly regulate the plasma Pi concentration. A high Pi load induces expression and secretion of the phosphaturic hormones parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) that enhance urinary Pi excretion and prevent the onset of hyperphosphatemia. How FGF23 secretion from bone is increased by a high Pi load and the setpoint of the plasma Pi concentration, however, are unclear. Here, we investigated the role of Transmembrane protein 174 (Tmem174) and observed evidence for gene co-expression networks in NaPi2a and NaPi2c function. Tmem174 is localized in the renal proximal tubules and interacts with NaPi2a, but not NaPi2c. In Tmem174-knockout (KO) mice, the serum FGF23 concentration was markedly increased but increased Pi excretion and hypophosphatemia were not observed. In addition, Tmem174-KO mice exhibit reduced NaPi2a responsiveness to FGF23 and PTH administration. Furthermore, a dietary Pi load causes marked hyperphosphatemia and abnormal NaPi2a regulation in Tmem174-KO mice. Thus, Tmem174 is thought to be associated with FGF23 induction in bones and the regulation of NaPi2a to prevent an increase in the plasma Pi concentration due to a high Pi load and kidney injury.

Regulation of Phosphate Transporters and Novel Regulator of Phosphate Metabolism

“…However, the Tmem174 function and role have not been clarified. Tmem174 knockout mice fed with standard mouse chow showed an oversecretion of PTH and FGF23 despite normal Pi levels in the blood and urinary Pi excretion (Figure 2A-D) [60]. Renal NaPi2a expression was not suppressed, although NaPi2c expression was markedly reduced in Tmem174 knockout mice compared with wild-type (WT) mice (Figure 2E).…”

“…Recently, transmembrane protein (Tmem) 174 has been reported as a novel regulator of NaPi2a degradation [60]. Tmem174 was identified as a molecule associated with slc34a1 and slc34a3 gene expression through in silico analysis.…”

“…The Tmem174 protein consists of 243 amino acids and has two transmembrane domains (Figure 1A). Mouse Tmem174 mRNA was significantly higher in the kidney than in other tissues (Figure 1B), and the protein is localized to the apical membrane of the renal proximal tubules (Figure 1C) [60]. However, the Tmem174 function and role have not been clarified.…”

“…Renal NaPi2a expression was not suppressed, although NaPi2c expression was markedly reduced in Tmem174 knockout mice compared with wild-type (WT) mice (Figure 2E). Tmem174 binds to NaPi2a, but not to NHERF1 without NaPi2a, and Tmem174 deficiency is limited to the control function of NaPi2a [60]. Tmem174 KO mice were shown to lead to PTH/FGF23 resistance in renal NaPi2a.…”

Understanding renal phosphate handling: unfinished business

“…Two groups recently simultaneously published on the role of Tmem174 (transmembrane protein 174) in the downregulation of the SLC34 proteins by PTH and FGF23 [10 ▪▪ ,11 ▪▪ ]. Using a COXPRESdb search strategy, Sasaki et al [10 ▪▪ ] determined that the genes for Npt2a and Npt2c showed significant co-expression with the gene for Tmem174. Tmem174 protein expression was high in kidney tissue, increased by low phosphate diet, and decreased in mice lacking expression of either Npt2a or 2c.…”