Acute adaptation of renal phosphate transporters in the murine kidney to oral phosphate intake requires multiple signals

Abstract

Aims Dietary inorganic phosphate (Pi) modulates renal Pi reabsorption by regulating the expression of the NaPi‐IIa and NaPi‐IIc Pi transporters. Here, we aimed to clarify the role of several Pi‐regulatory mechanisms including parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23) and inositol hexakisphosphate kinases (IP6‐kinases) in the acute regulation of NaPi‐IIa and NaPi‐IIc. Methods Wildtype (WT) and PTH‐deficient mice (PTH‐KO) with/without inhibition of FGF23 signalling were gavaged with Pi/saline and examined at 1, 4 and 12 h. Results Pi‐gavage elevated plasma Pi and decreased plasma Ca2+ in both genotypes after 1 h Within 1 h, Pi‐gavage decreased NaPi‐IIa abundance in WT and PTH‐KO mice. NaPi‐IIc was downregulated 1 h post‐administration in WT and after 4 h in PTH‐KO. PTH increased after 1 h in WT animals. After 4 h Pi‐gavage, FGF23 increased in both genotypes being higher in the KO group. PTHrp and dopamine were not altered by Pi‐gavage. Blocking FGF23 signalling blunted PTH upregulation in WT mice and reduced NaPi‐IIa downregulation in PTH‐KO mice 4 h after Pi‐gavage. Inhibition of IP6‐kinases had no effect. Conclusions (1) Acute downregulation of renal Pi transporters in response to Pi intake occurs also in the absence of PTH and FGF23 signalling, (2) when FGF23 signalling is blocked, a partial contribution of PTH is revealed, (3) IP6 kinases, intracellular Pi‐sensors in yeast and bacteria, are not involved, and (4) Acute Pi does not alter PTHrp and dopamine. Thus, signals other than PTH, PTHrp, FGF23 and dopamine contribute to renal adaption.

Sorting out the rapid renal response to an oral phosphate load

“…Insulin may also play a role in this response; while this was not measured in the current experimental series, insulin was not found to increase following acute Pi loads in rats and humans 4,6 . Factors associated with FGF23 signaling were also investigated by Daryadel et al and an early response gene associated with FGF23 signaling was found to increase 4 h after Pi loading in both genotypes, in line with an increase in FGF23 levels 3 . Interestingly, FGF23 signaling was increased in Pth ‐deficient mice already after 1 h, before changes in FGF23 levels could be observed.…”

“…6 In the current study, Daryadel et al explore the effect of acute Pi loading via gavage in wild-type mice and utilize transgenic mice lacking the Pth gene to define PTHindependent effects in this response. 3 In contrast to the previous experiments in rats, an acute Pi load via gavage in mice leads to substantial initial elevations in plasma Pi similar to that seen with intravenous infusion in rats and both intravenous and duodenal infusions in humans. 4,6 Using a comprehensive approach of functional measurements that include renal excretion of Pi and expression of the Na + / Pi cotransporters in renal brush border membrane isolates as well as relevant hormones and transmitters, Daryadel et al sought to understand in further detail the mechanisms driving the renal defense against Pi overload.…”

“…4,6 Factors associated with FGF23 signaling were also investigated by Daryadel et al and an early response gene associated with FGF23 signaling was found to increase 4 h after Pi loading in both genotypes, in line with an increase in FGF23 levels. 3 Interestingly, FGF23 signaling was increased in Pth-deficient mice already after 1 h, before changes in FGF23 levels could be observed. The mechanism for this early increase in FGF23 signaling remains to be elucidated.…”

“…1,2 It is therefore important to understand the Pi-sensing mechanisms that defend the body against hyperphosphatemia, and in the present issue of Acta Physiologica, Daryadel et al use transgenic mice and pharmacological tools to interrogate signaling mechanisms underlying the acute renal adaption to an oral Pi load. 3 The kidneys are central in the acute adaption to dietary Pi loads and act by reducing the renal reabsorption of Pi. They do so by altering the abundance of Pi transport proteins, expressed in the apical brush border membrane of the proximal tubule.…”

“…In the current study, Daryadel et al explore the effect of acute Pi loading via gavage in wild‐type mice and utilize transgenic mice lacking the Pth gene to define PTH‐independent effects in this response 3 . In contrast to the previous experiments in rats, an acute Pi load via gavage in mice leads to substantial initial elevations in plasma Pi similar to that seen with intravenous infusion in rats and both intravenous and duodenal infusions in humans 4,6 .…”