The intestinal phosphate transporter NaPi-IIb (Slc34a2) is required to protect bone during dietary phosphate restriction

Abstract

NaPi-IIb/Slc34a2 is a Na+-dependent phosphate transporter that accounts for the majority of active phosphate transport into intestinal epithelial cells. Its abundance is regulated by dietary phosphate, being high during dietary phosphate restriction. Intestinal ablation of NaPi-IIb in mice leads to increased fecal excretion of phosphate, which is compensated by enhanced renal reabsorption. Here we compared the adaptation to dietary phosphate of wild type (WT) and NaPi-IIb−/− mice. High phosphate diet (HPD) increased fecal and urinary excretion of phosphate in both groups, though NaPi-IIb−/− mice still showed lower urinary excretion than WT. In both genotypes low dietary phosphate (LDP) resulted in reduced fecal excretion and almost undetectable urinary excretion of phosphate. Consistently, the expression of renal cotransporters after prolonged LDP was similar in both groups. Plasma phosphate declined more rapidly in NaPi-IIb−/− mice upon LDP, though both genotypes had comparable levels of 1,25(OH)2vitamin D3, parathyroid hormone and fibroblast growth factor 23. Instead, NaPi-IIb−/− mice fed LDP had exacerbated hypercalciuria, higher urinary excretion of corticosterone and deoxypyridinoline, lower bone mineral density and higher number of osteoclasts. These data suggest that during dietary phosphate restriction NaPi-IIb-mediated intestinal absorption prevents excessive demineralization of bone as an alternative source of phosphate.

Intestinal epithelial ablation of Pit‐2/Slc20a2 in mice leads to sustained elevation of vitamin D3 upon dietary restriction of phosphate

“…We have already reported that wild-type and intestinal-specific NaPi-IIb-deficient mice retained/restored normophosphataemia after 14 days under low dietary Pi, a response that in wild type seemed to depend solely on higher renal reabsorption, though increased bone resorption may also be required in NaPi-IIb-depleted mice. 18 Similar to the work presented here, no differences in serum or urinary Pi were reported between wild-type mice and mice with full ablation of Pit-2 after 1 week of low (0.05%), normal (0.55%) or high Pi (1.65%) diets, except for a reduction in serum Pi in mutant mice fed on high Pi compared with wild types. 25 In our model, the compensatory reduction in urinary excretion of Pi in response to low dietary Pi reflects upregulation of NaPi-IIa and NaPi-IIc, the Slc34 cotransporters expressed in renal proximal tubules that are responsible for reabsorption of Pi from the primary urine (for review see Ref.36).…”

“…13 The observation that 1,25(OH) 2 D 3 levels were similar in +/+ mice fed standard and low Pi diets is in agreement with previous reports showing that the increase of 1,25(OH) 2 D 3 triggered by low dietary Pi is transient, with higher values detected 3 days after dietary restriction and normalizing thereafter. 18 However, in the absence of intestinal epithelial Pit-2, 1,25(OH) 2 D 3 remains high even after 2 weeks feeding on low Pi. Although we could not identify the mechanism responsible (either increased synthesis/Cyp27b1 and/or reduced catabolism/Cyp24a1), this finding indicates that in the absence of Pit-2 in enterocytes, mice depend upon sustained elevation of 1,25(OH) 2 D 3 to maintain normophosphataemia when challenged with low dietary Pi.…”

“…4 In agreement with this large contribution, maintenance of normophosphataemia in Pi-deprived NaPi-IIb −/− mice requires mobilization of skeletal Pi. 18 Pit-1 and Pit-2 were originally identified as membrane receptors for gibbon ape leukaemia virus (Glvr-1) 19 and murine amphotropic retrovirus (Ram-1), 20 respectively, though their function as Na + /Pi cotransporters was soon recognized. 20,21 Both SLC20 cotransporters have affinities for Na + (50 mmol/L) and Pi (100 µmol/L) in the same range as those displayed by NaPi-IIb but, unlike the SLC34 members, Pit transporters transport preferentially monovalent (H 2 PO 4 − ) instead of divalent (HPO 4 2− ) Pi.…”

The role of SLC34A2 in intestinal phosphate absorption and phosphate homeostasis

“…1a). In this context, dietary phosphate restriction would not only increase NaPi-IIb-mediated transport but also lower the gradient for passive transport across the epithelium, prompting a rapid switch from the dominance of one pathway to the other [36]. Importantly, the idea that NaPi-IIb-mediated transport is only dominant during dietary restriction is not new.…”

Clinical aspects of the phosphate transporters NaPi-IIa and NaPi-IIb: mutations and disease associations

“…Several mouse models of Slc34a2 deletion have been generated, mostly to characterize the role of NaPi-IIb in intestine [32,85]. These models demonstrate that NaPi-IIb is the main cotransporter in the ileum, but its absence has only mild consequences on Pi and hormonal levels [53,32,85]. In contrast, a lung epithelium specific NaPi-IIb mouse had higher Pi concentrations in the bronchoalveolar fluid with microcrystals, invasion of macrophages and signs of inflammation and fibrosis [86].…”