X-linked hypophosphatemic Gy mice: renal tubular maximum for phosphate vs. brush-border transport after low-P diet

Dulde

2004

Physiological Genomics

The mechanism for the renal adaptation to low-phosphate diets is not well understood. Whether the Hyp mutation of the Phex gene blocks this adaptation is also not clear. To gain further insight into this, 5-wk-old normal and Hyp mice were fed a control (1.0% P) or low-phosphate diet (0.03% P) for 3-5 days. Renal RNA was hybridized to Affymetrix U74Av2 microarrays (5 arrays/group). Of the 5,719 detectable genes on each array, 290 responded significantly (P < 0.01) to low-phosphate diet in normal mice. This was reduced significantly (P < 0.001) to 7 in the Hyp mice. This suggested that the adaptations of the normal kidney to a low-phosphate environment were blocked by the Hyp mutation. The Npt2 phosphate transporter, vitamin D 1alpha- and 24-hydroxylases, and calbindins D9K and D28K responded in the expected fashion. Genes with significant (P < 0.05) diet-by-genotype interaction were analyzed by GenMAPP and MAPPFinder. This revealed a cluster of differentially expressed genes associated with microtubule-based processes. Most alpha- and beta-tubulins and most kinesins had responses to low-phosphate diet in normal mice which were abolished or reversed in Hyp mice. In summary, renal adaptation to low-phosphate diet involved changes in the mRNA expression of specific genes. Disruption of these responses in Hyp mice may contribute to their abnormal phosphate homeostasis.

Section: Discussionmentioning

confidence: 99%

The genomic response of the mouse kidney to low-phosphate diet is altered in X-linked hypophosphatemia

Dulde

2004

Physiological Genomics

“…TmP for each mouse was the peak reabsorption rate among were fed Teklad Mouse Breeder Diet (W) No. 8626 (Harlan, Madison, the four collection periods [16]. Data were discarded from all collection Wisc., USA) and Teklad Rodent Diet (W) No.…”

Section: Methodsmentioning

confidence: 99%

“…The procedure for this experiment was modified from methods of addition, recent studies in humans [8] and mice [9] with Mü hlbauer et al [4], LeClaire et al [12], and Thornton et al [16]. Eight XLH have found that there are mutations in the PEX treatment groups (four doses ¶two genotypes) were studied with gene, renamed PHEX [10] ( phosphate-regulating gene approximately 10 animals per group.…”

Section: Tmp Measurementmentioning

confidence: 99%

Isoproterenol Increases Renal Tubular Reabsorption of Phosphate in X-Linked Hypophosphatemic (<i>Hyp</i>) Mice

Thornton

Mineral Electrolyte Metab

1999

Hypophosphatemic (Hyp) mice have a reduced renal retention of phosphate. The β-adrenergic agonist isoproterenol reverses phosphaturia induced by parathyroid hormone in the rat. This study determined whether isoproterenol could raise the renal tubular maximum transport of phosphate (TmP) in Hyp mice. Male 10- to 12-week-old normal and Hyp mice were infused with ³H-inulin and isoproterenol (0.0, 0.25, 0.5 and 1.0 µg/kg/min) in 0.9% NaCl. Glomerular filtration rate, plasma phosphate, urinary phosphate excretion, TmP, urinary sodium excretion, and urinary cyclic adenosine monophosphate were measured. As expected, Hypcontrols (0.0 dose) had a TmP which was significantly below that of normal controls: 1.15±(SEM) 0.6 (n = 9) versus 2.13±0.10 (n = 11) µmol P/ml glomerular filtrate (p<0.001). Isoproterenol at doses of 0.5 and 1.0 µg/kg/min elevated the TmP of Hyp mice to the level of normal controls: 1.94±0.19 (n = 7) and 1.98±0.10 (n = 9) µmol P/ml glomerular filtrate, respectively. These results indicate that the low tubular reabsorption of phosphate in Hyp mice is not due to a fixed low level of phosphate transport, but to decreased stimulation of phosphate transporters, since Hyp mouse kidneys increase phosphate reabsorption with suitable stimulus.

Renal expression of Na+-phosphate cotransporter mRNA and protein: Effect of the Gy mutation and low phosphate diet

et al. 1996

The X-linked Gy mutation is closely linked, but not allelic, to Hyp and is characterized by rickets, hypophosphatemia, decreased renal tubular maximum for phosphate (Pi) reabsorption (TmP) and a specific reduction in renal brush-border membrane (BBM) Na+-Pi cotransport. Gy mice, like their normal littermates, respond to a low-Pi diet with an increase in BBM Na+-Pi cotransport, but fail to show an adaptive increase in Tmp. Using an antibody raised against the NH2 terminal peptide of the rat renal-specific Na+-Pi cotransporter (NaPi-2) and a NaPi-2 cDNA probe, we examined the effect of the Gy mutation and low-Pi diet (0.03% Pi) on NaPi-2 protein and mRNA abundance. The reduction in BBM Na+-Pi cotransport in Gy mice (51 +/- 5% of normal, P < 0.05) was associated with a decrease in NaPi-2 protein (46 +/- 12% of normal, P < 0.05) and mRNA abundance (76 +/- 5%, P < 0.05). The low-Pi diet elicited a two- to three-fold increase in Na+-Pi cotransport in both normal and Gy mice that was accompanied by a large increase in NaPi-2 protein (10.2-fold in normal and 16.9-fold in Gy mice) and a modest increase in NaPi-2 mRNA (1.3-fold in both mouse strains, P < 0.05). The present data demonstrate that (1) the renal defect in BBM Pi transport in Gy mice can be ascribed to a deficit in NaPi-2 protein and mRNA abundance, (2) both normal and Gy mice respond to low Pi with an adaptive increase in NaPi-2 protein that exceeds the increase in Na+-Pi cotransport activity and NaPi-2 mRNA, (3) the adaptive increase in NaPi-2 protein and mRNA are not sufficient for the overall increase in TmP following Pi restriction.