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

Departments of ¹Pediatrics and ²Human Genetics, McGill University, and ³Montreal Children's Hospital Research Institute, Montreal, Quebec, H3Z 2Z3 Canada; and ⁴Department of Nutrition, School of Medicine, Tokushima University, Tokushima City, 770-8503 Japan

Submitted 15 July 2003 ; accepted in final form 26 August 2003

The present study was undertaken to define the mechanisms governing the regulation of the novel renal brush-border membrane (BBM) Na-phosphate (P_i) 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-P_i 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 -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. P_i 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. P_i 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-P_i 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-P_i cotransport in the knockout model. Finally, our data indicate that loss of Phex function abrogates renal Npt2c protein expression.

hypophosphatemia; mouse; Phex; Na-P_i cotransporter type I; low phosphate

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