Differential effects of Npt2a gene ablation and X-linked Hyp mutation on renal expression of Npt2c

Abstract

The present study was undertaken to define the mechanisms governing the regulation of the novel renal brush-border membrane (BBM) Na-phosphate (Pi) cotransporter designated type IIc (Npt2c). To address this issue, the renal expression of Npt2c was compared in two hypophosphatemic mouse models with impaired renal BBM Na-Pi cotransport. In mice homozygous for the disrupted Npt2a gene (Npt2-/-), BBM Npt2c protein abundance, relative to actin, was increased 2.8-fold compared with Npt2+/+ littermates, whereas a corresponding increase in renal Npt2c mRNA abundance, relative to beta-actin, was not evident. In contrast, in X-linked Hyp mice, which harbor a large deletion in the Phex gene, the renal abundance of both Npt2c protein and mRNA was significantly decreased by 80 and 50%, respectively, relative to normal littermates. Pi deprivation elicited a 2.5-fold increase in BBM Npt2c protein abundance in Npt2+/+ mice but failed to elicit a further increase in Npt2c protein in Npt2-/- mice. Pi restriction led to an increase in BBM Npt2c protein abundance in both normal and Hyp mice without correcting its renal expression in the mutants. In summary, we report that BBM Npt2c protein expression is differentially regulated in Npt2-/- mice and Hyp mice and that the Npt2c response to low-Pi challenge differs in both hypophosphatemic mouse strains. We demonstrate that Npt2c protein is maximally upregulated in Npt2-/- mice and suggest that Npt2c likely accounts for residual BBM Na-Pi cotransport in the knockout model. Finally, our data indicate that loss of Phex function abrogates renal Npt2c protein expression.

The phosphate transporter NaPi-IIa determines the rapid renal adaptation to dietary phosphate intake in mouse irrespective of persistently high FGF23 levels

“…In contrast, Na + -dependent Pi-uptake into BBMV was very low and remained unchanged in NaPi-IIa -/-mice whatever the diet. The remaining activity in knock-out BBM is approximately reduced to 30 % under chronic high phosphate diet which is similar to what was described earlier [50,56]. This result indicates that NaPi-IIc and Pit-2 transport activities are low in mice and may already be maximally stimulated in NaPi-IIa deficient mice as compensatory mechanism.…”

Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes

“…However, almost half of these mice die before weaning, and those that do survive maintain serum phosphate levels that are 65-80% of those of their wild-type littermates, whereas the mouse models in our studies had a 50% decrease in their serum phosphate levels. It is notable that the surviving Npt2a knockout mice have a 2.5-fold increase in Npt2c protein expression in the kidney, suggesting a compensatory mechanism that may maintain circulating phosphate levels closer to the normal range than that observed in the Hyp mice, in whom an 80% decrease in Npt2c protein levels is seen (26). These observations implicate a threshold in the circulating phosphate levels, below which impairment of hypertrophic chondrocyte apoptosis is observed.…”

The emerging role of the fibroblast growth factor-23–klotho axis in renal regulation of phosphate homeostasis

“…Furthermore, Na/Pi-2a K/K mice also develop hypercalcemia, hypercalciuria, and have low serum level of PTH (Chau et al 2003). Perhaps as a compensatory effect, the Na/Pi-2c protein is markedly increased in the brush-border membrane of Na/Pi-2a K/K mice (Tenenhouse et al 2003). Known regulators of renal phosphate reabsorption, including dietary phosphate intake or PTH administration have no significant effect on renal phosphate transport in Na/Pi-2a K/K mice, suggesting that Na/Pi-2a is the main regulatory molecule which handles renal phosphate transport activities in the mice (Tenenhouse 2005).…”