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Response of Npt2a knockout mice to dietary calcium and phosphorus.

ABSTRACT: Mutations in the renal sodium-dependent phosphate co-transporters NPT2a and NPT2c have been reported in patients with renal stone disease and nephrocalcinosis, but the relative contribution of genotype, dietary calcium and phosphate to the formation of renal mineral deposits is unclear. We previously reported that renal calcium phosphate deposits persist and/or reappear in older Npt2a-/- mice supplemented with phosphate despite resolution of hypercalciuria while no deposits are seen in wild-type (WT) mice on the same diet. Addition of calcium to their diets further increased calcium phosphate deposits in Npt2a-/-, but not WT mice. The response of PTH to dietary phosphate of Npt2a-/- was blunted when compared to WT mice and the response of the urinary calcium x phosphorus product to the addition of calcium and phosphate to the diet of Npt2a-/- was increased. These finding suggests that Npt2a-/- mice respond differently to dietary phosphate when compared to WT mice. Further evaluation in the Npt2a-/- cohort on different diets suggests that urinary calcium excretion, plasma phosphate and FGF23 levels appear to be positively correlated to renal mineral deposit formation while urine phosphate levels and the urine anion gap, an indirect measure of ammonia excretion, appear to be inversely correlated. Our observations in Npt2a-/- mice, if confirmed in humans, may be relevant for the optimization of existing and the development of novel therapies to prevent nephrolithiasis and nephrocalcinosis in human carriers of NPT2a and NPT2c mutations.

SUBMITTER: Li Y

PROVIDER: S-EPMC5407772 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Response of Npt2a knockout mice to dietary calcium and phosphorus.

Li Yuwen Y Caballero Daniel D Ponsetto Julian J Chen Alyssa A Zhu Chuanlong C Guo Jun J Demay Marie M Jüppner Harald H Bergwitz Clemens C

PloS one 20170427 4

Mutations in the renal sodium-dependent phosphate co-transporters NPT2a and NPT2c have been reported in patients with renal stone disease and nephrocalcinosis, but the relative contribution of genotype, dietary calcium and phosphate to the formation of renal mineral deposits is unclear. We previously reported that renal calcium phosphate deposits persist and/or reappear in older Npt2a-/- mice supplemented with phosphate despite resolution of hypercalciuria while no deposits are seen in wild-type ...[more]

PMID: 28448530

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Project description:The quality and strength of the skeleton is regulated by mechanical loading and adequate mineral intake of calcium (Ca) and phosphorus (P). Whole body vibration (WBV) has been shown to elicit adaptive responses in the skeleton, such as increased bone mass and strength. This experiment was designed to determine the effects of WBV and dietary Ca and P on bone microarchitecture and turnover. A total of 26 growing pigs were utilized in a 60-d experiment. Pigs were randomly assigned within group to a 2 × 2 factorial design with dietary Ca and P concentration (low and adequate) as well as WBV. The adequate diet was formulated to meet all nutritional needs according to the NRC recommendations for growing pigs. Low Ca, P diets had 0.16% lower Ca and 0.13% lower P than the adequate diet. Pigs receiving WBV were vibrated 30 min/d, 3 d/wk at a magnitude of 1 to 2 mm and a frequency of 50 Hz. On days 0, 30, and 60, digital radiographs were taken to determine bone mineral content by radiographic bone aluminum equivalency (RBAE) and serum was collected to measure biochemical markers of bone formation (osteocalcin, OC) and bone resorption (carboxy-terminal collagen crosslinks, CTX-I). At day 60, pigs were euthanized and the left third metacarpal bone was excised for detailed analysis by microcomputed tomography (microCT) to measure trabecular microarchitecture and cortical bone geometry. Maximum RBAE values for the medial or lateral cortices were not affected (P > 0.05) by WBV. Pigs fed adequate Ca and P tended (P = 0.10) to have increased RBAE max values for the medial and lateral cortices. WBV pigs had significantly decreased serum CTX-1 concentrations (P = 0.044), whereas animals fed a low Ca and P diet had increased (P < 0.05) OC concentrations. In bone, WBV pigs showed a significantly lower trabecular number (P = 0.002) and increased trabecular separation (P = 0.003), whereas cortical bone parameters were not significantly altered by WBV or diet (P > 0.05). In summary, this study confirmed the normal physiological responses of the skeleton to a low Ca, P diet. Interestingly, although the WBV protocol utilized in this study did not elicit any significant osteogenic response, decreases in CTX-1 in response to WBV may have been an early local adaptive bone response. We interpret these data to suggest that the frequency and amplitude of WBV was likely sufficient to elicit a bone remodeling response, but the duration of the study may not have captured the full extent of an entire bone remodeling cycle.

Project description:BackgroundCalcium (Ca) and phosphorus (P) are essential nutrients that are linked to a large array of biological processes. Disturbances in Ca and P homeostasis in chickens are associated with a decline in growth and egg laying performance and environmental burden due to excessive P excretion rates. Improved utilization of minerals in particular of P sources contributes to healthy growth while preserving the finite resource of mineral P and mitigating environmental pollution. In the current study, high performance Lohmann Selected Leghorn (LSL) and Lohmann Brown (LB) hens at peak laying performance were examined to approximate the consequences of variable dietary Ca and P supply. The experimental design comprised four dietary groups with standard or reduced levels of either Ca or P or both (n = 10 birds per treatment group and strain) in order to stimulate intrinsic mechanisms to maintain homeostasis. Jejunal transcriptome profiles and the systemic endocrine regulation of mineral homeostasis were assessed (n = 80).ResultsEndogenous mechanisms to maintain mineral homeostasis in response to variations in the supply of Ca and P were effective in both laying hen strains. However, the LSL and LB appeared to adopt different molecular pathways, as shown by circulating vitamin D levels and strain-specific transcriptome patterns. Responses in LSL indicated altered proliferation rates of intestinal cells as well as adaptive responses at the level of paracellular transport and immunocompetence. Endogenous mechanisms in LB appeared to involve a restructuring of the epithelium, which may allow adaptation of absorption capacity via improved micro-anatomical characteristics.ConclusionsThe results suggest that LSL and LB hens may exhibit different Ca, P, and vitamin D requirements, which have so far been neglected in the supply recommendations. There is a demand for trial data showing the mechanisms of endogenous factors of Ca and P homeostasis, such as vitamin D, at local and systemic levels in laying hens.

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Response of Npt2a knockout mice to dietary calcium and phosphorus.

Publications

Response of Npt2a knockout mice to dietary calcium and phosphorus.

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