Fibroblast growth factor‐23 and parathyroid hormone suppress small intestinal magnesium absorption

Abstract

In the present study, we examined the systemic and direct effects of parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23) on duodenal, jejunal, and ileal Mg 2+ absorption. The rats were injected with FGF-23 or PTH for 5 h before collecting the duodenum, jejunum, and ileum for Mg 2+ transport analysis in Ussing chambers. The duodenum, jejunum, and ileum were directly exposed to FGF-23, PTH, or FGF-23 plus PTH with or without cell signaling inhibitors for 150 min in Ussing chambers prior to performing the Mg 2+ transport study.The small intestinal tissues were also subjected to western blot analyses for FGF receptor (FGFR), PTH receptor (PTHR), Klotho, transient receptor potential melastatin 6 (TRPM6), and cyclin as well as the cystathionine βsynthase domain divalent metal cation transport mediator 4 (CNNM4) expression. The small intestine abundantly expressed FGFR and PTHR proteins, whereas, Klotho was not expressed in rat small intestine. Systemic PTH or FGF-23 injection significantly suppressed transcellular Mg 2+ transport in the duodenum and jejunum. Direct FGF-23-, PTH-, or FGF-23 plus PTH exposure also suppressed transcellular Mg 2+ absorption in the duodenum and jejunum. There was no additional inhibitory effect of PTH and FGF-23 on intestinal Mg 2+ absorption. The inhibitory effect of PTH, FGF-23, or FGF-23 plus PTH was abolished by Gö 6850. Systemic PTH-or FGF-23-injection significantly decreased membranous TRPM6 expression, but increased cytosolic CNNM4 expression in the duodenum, jejunum, and ileum. In the present study, we propose a novel magnesiotropic action of PTH and FGF-23 by modulating small intestinal Mg 2+ absorption.

Mass spectrometric analysis of TRPM6 and TRPM7 from small intestine of omeprazole-induced hypomagnesemic rats

“…CNNM4 mediates basolateral Mg 2+ extrusion and is implicated in small intestinal transcellular Mg 2+ absorption (38). Recently, fibroblast growth factor-23 (FGF-23) has been reported to systemically and directly increase membrane CNNM4 expression in the duodenum and the jejunum (12) and our PPIH rat model shows significantly higher plasma FGF-23 compared to controls (12). Therefore, the observed increase in membrane CNNM4 in the duodenum and the jejunum of PPIH rats may involve an FGF-23-dependent mechanism.…”

“…It has been previously proposed that the small intestine absorbs Mg 2+ solely through an un-regulated paracellular pathway because the TRPM6 gene was not detected in the murine small intestine ( 3 , 10 ); however, we have previously demonstrated that the duodenum, the jejunum, and the ileum absorb Mg 2+ through both transcellular and paracellular mechanisms ( 7 , 8 ). Further, TRPM6 is markedly expressed in duodenal, jejunal, and ileal tissues in rats ( 7 ) and humans ( 11 ), and a recent study has reported that fibroblast growth factor-23 and parathyroid hormone systemically and directly regulate both transcellular Mg 2+ absorption and membrane TRPM6 expression in the duodenum and the jejunum ( 12 ).…”

Current opinion on the regulation of small intestinal magnesium absorption

“…However, a study from the same group showed positive immunofluorescence staining of TRPM6 protein in the absorptive cells along the brush border membrane of the villi in the duodenum[ 10 ]. Another group has proposed that the small intestinal epithelium absorbs Mg 2+ through transcellular active and paracellular passive transport mechanisms[ 11 - 13 ]. In an Ussing chamber study, transport of transcellular and paracellular Mg 2+ was detected in the duodenum, jejunum, and ileum[ 11 - 13 ].…”

“…Another group has proposed that the small intestinal epithelium absorbs Mg 2+ through transcellular active and paracellular passive transport mechanisms[ 11 - 13 ]. In an Ussing chamber study, transport of transcellular and paracellular Mg 2+ was detected in the duodenum, jejunum, and ileum[ 11 - 13 ]. The proposed mechanism of small intestinal Mg 2+ absorption is shown in Figure 1 .…”

“…However, the heterodimer TRPM6/7 channels do not respond to physiological intracellular Mg 2+ and Mg·ATP[ 17 , 19 ]; thus, continuous epithelial Mg 2+ absorption can occur through the TRPM6/7 channel, regardless of intracellular Mg 2+ and concentrations. Basolateral Mg 2+ extrusion from the small intestinal epithelium occurs through cystathionine β-synthase domain divalent metal cation transport mediator 4[ 11 - 13 , 20 ] by means of a sodium (Na + ) gradient-dependent secondary active transport[ 20 ]. However, mutation of cystathionine β-synthase domain divalent metal cation transport mediator 4 does not affect the plasma concentration in humans[ 21 , 22 ], suggesting that other Mg 2+ extrusion mechanisms probably occur.…”