Intestinal Npt2b Plays a Major Role in Phosphate Absorption and Homeostasis

Abstract

Intestinal phosphate absorption occurs through both a paracellular mechanism involving tight junctions and an active transcellular mechanism involving the type II sodium-dependent phosphate cotransporter NPT2b (SLC34a2). To define the contribution of NPT2b to total intestinal phosphate absorption, we generated an inducible conditional knockout mouse, Npt2b Inorganic phosphate is an essential mineral critical for cellular processes and bone mineralization. Severe disruptions in serum phosphate have pathologic consequences. 1,2 Hypophosphatemic disorders are associated with rickets, osteomalacia, and a host of secondary dysfunctions. 3 In contrast, hyperphosphatemia associated with chronic kidney disease (CKD) is linked tightly to increased risk of cardiovascular morbidity and mortality. 4 -6 Recent studies show that elevated phosphate concentrations within the high normal range in individuals with functional kidneys also are correlated with increased cardiovascular risk and mortality. 7,8 Thus, an elevated serum phosphate level is an emerging health risk. Despite the importance of maintaining a relatively narrow serum phosphate range, nearly 70% of dietary phosphate is absorbed, resulting in transient postprandial increases in serum phosphate concentrations. 9 Normalization of serum phosphate appears to be managed primarily within the renal proximal tubule by the type II sodium-dependent phosphate cotransporters NPT2a (SLC34a1) and NPT2c (SLC34a3). Genetic knockout mouse models demonstrate that 80% and 20% of total urinary phosphorus are managed by the Npt2a and Npt2c transporters, respectively. 10,11 Chronic and acute regulation of these renal transporters is modulated by changes in dietary and serum phosphate

Npt2b Deletion Attenuates Hyperphosphatemia Associated with CKD

“…6 At 2 weeks, WT mice were significantly hyperphosphatemic, whereas Npt2b 2/2 mice had a slightly lower serum phosphate (Supplemental Figure 1). In contrast, sevelamer treatment led to a significant decrease in Npt2b 2/2 mice relative to WT treated mice (Supplemental Figure 1).…”

“…6 These studies utilized our previously characterized model in which Npt2b deletion in adult mice is driven by a tamoxifen-inducible CRE system. 6 Parallel studies were performed in animals fed 1% sevelamer carbonate to compare relative effects of deleting Npt2b with phosphate sequestration. Immunostaining of intestinal sections clearly detected Npt2b protein expression on the villi surfaces of ileum in all WT but not Npt2b 2/2 mice ( Figure 1A).…”

“…Most importantly, Npt2b 2/2 mice maintained serum phosphorus within the normal range by decreasing the phosphaturic hormone, fibroblast growth factor 23 (FGF23), upregulating renal Npt2a protein expression and subsequently decreasing urinary phosphorus excretion. 6 These studies demonstrated that Npt2b is an important route for phosphate absorption and participates in the regulation of renal phosphate handling.…”

“…[3][4][5] We have recently challenged this dogma by conditionally deleting the intestinal sodium-dependent phosphate cotransporter, Npt2b, in adult mice. 6 By mimicking postprandial conditions to maximize contributions of both passive and active transport, Npt2b-dependent phosphate transport was shown to contribute to as much as 50% of the total phosphorus uptake. 6 Using the everted sac method, we also confirmed that .90% of active transport occurs through Npt2b.…”

“…6 By mimicking postprandial conditions to maximize contributions of both passive and active transport, Npt2b-dependent phosphate transport was shown to contribute to as much as 50% of the total phosphorus uptake. 6 Using the everted sac method, we also confirmed that .90% of active transport occurs through Npt2b. Most importantly, Npt2b 2/2 mice maintained serum phosphorus within the normal range by decreasing the phosphaturic hormone, fibroblast growth factor 23 (FGF23), upregulating renal Npt2a protein expression and subsequently decreasing urinary phosphorus excretion.…”