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1 Department of Pediatrics, McGill University, Montreal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
2 Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
3 Department of Nutrition, School of Medicine, Tokushima University, Tokushima, Japan
* To whom correspondence should be addressed. E-mail: harriet.tenenhouse{at}mcgill.ca.
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 when compared to Npt2+/+ littermates whereas a corresponding increase in renal Npt2c mRNA abundance, relative to 
-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.
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