Renal Fanconi Syndrome and Hypophosphatemic Rickets in the Absence of Xenotropic and Polytropic Retroviral Receptor in the Nephron

Ansermet, Camille; Moor, Matthias B.; Centeno, Gabriel; Auberson, Muriel; Hu, Dorothy; Baron, Roland; Nikolaeva, Svetlana; Haenzi, Barbara; Katanaeva, N.; Gautschi, Ivan; Katanaev, Vladimir L.; Rotman, Samuel; Koesters, Robert; Schild, Laurent; Pradervand, Sylvain; Bonny, Olivier; Firsov, Dmitri

doi:10.1681/asn.2016070726

Cited by 61 publications

(47 citation statements)

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“…As examples in the kidney, Type II sodium-dependent phosphate cotransporters are regulated by dietary phosphate supply (Bourgeois et al, 2013), and gene expression of Trpv5 encoding a renal calcium transport protein is controlled by 1,25(OH) 2 -vitamin D 3 (Hoenderop et al, 2001). As examples in the bone, Fgf23 expression is stimulated by 1,25(OH) 2 -vitamin D 3 (Liu et al, 2006) or PTH (Kawata et al, 2007), while dietary phosphate restriction or renal phosphate-wasting disorders reduce Fgf23 expression (Vervloet et al, 2011, Schlingmann et al, 2016, Ansermet et al, 2017. Even intravenous calcium loading in rats increased Fgf23 expression in bone and hormone concentrations in the serum (Shikida et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Memo1gene expression in kidney and bone is unaffected by dietary mineral load and calciotropic hormones

Moor

Bonny

2020

Preprint

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AbstractMediator of Cell Motility 1 (MEMO1) is an ubiquitously expressed modulator of cellular responses to growth factors including FGF23 signaling, and Memo1-deficient mice share some phenotypic traits with Fgf23- or Klotho-deficient mouse models. Here, we tested whether Memo1 gene expression is regulated by calciotropic hormones or by changing the dietary mineral load.MLO-Y4 osteocyte-like cells were cultured and treated with 1,25(OH)2-vitamin D3. Wildtype C57BL/6N mice underwent treatments with 1,25(OH)2-vitamin D3, parathyroid hormone (PTH), 17β-estradiol or vehicle. Other cohorts of C57BL/6N mice were fed diets varying in calcium or phosphate content. Expression of Memo1 and control genes was assessed by qPCR.1,25(OH)2-vitamin D3 caused an acute decrease in Memo1 transcript levels in vitro, but not in vivo. None of the hormones tested had an influence on Memo1 transcripts, whereas the assessed control genes reacted the expected way. Dietary interventions with calcium and phosphate did not affect Memo1 transcripts but altered the chosen control genes’ expression.We observed that Memo1 was not regulated by calciotropic hormones or change in mineral load, suggesting major differences between the regulation and physiological roles of Klotho, Fgf23 and Memo1.

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Section: Discussionmentioning

confidence: 99%

Memo1gene expression in kidney and bone is unaffected by dietary mineral load and calciotropic hormones

Moor

Bonny

2020

Preprint

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“…(23) Conditional inactivation of Xpr1 in renal tubules in mice will impair renal Pi reabsorption, which results in a reduced serum Pi level and bone mineralization. (34) Hence, in the Xpr1-deficient fetuses, although the abnormal placental Pi exchange might be a contributing factor, the XPR1 deficiency throughout all fetal tissues, especially in the kidneys and intestines, might be the main factor underlying the reduced Pi level in fetal serum and amniotic fluid and the reduction in fetal skeletal mineralization.…”

Section: Discussionmentioning

confidence: 99%

Murine Placental-Fetal Phosphate Dyshomeostasis Caused by an Xpr1 Deficiency Accelerates Placental Calcification and Restricts Fetal Growth in Late Gestation

Sun

et al. 2019

Journal of Bone and Mineral Research

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Phosphorus is a necessary component of all living organisms. This nutrient is mainly transported from the maternal blood to the fetus via the placenta, and insufficient phosphorus availability via the placenta disturbs the normal development of the fetus, especially fetal bone formation in late gestation. Key proteins (phosphate transporters and exporters) that are responsible for the maintenance of placental‐fetal phosphorus homeostasis have been identified. A deficiency in the phosphate transporter Pit2 has been shown to result in placental calcification and the retardation of fetal development in mice. What roles does XPR1 (the only known phosphate exporter) play in maintaining placental‐fetal phosphorus homeostasis? In this study, we found that Xpr1 expression is strong in the murine placenta and increases with age during gestation. We generated a global Xpr1 knockout mouse and found that heterozygous (Xpr1+/−) and homozygous (Xpr1−/−) fetuses have lower inorganic phosphate (Pi) levels in amniotic fluid and serum and a decreased skeletal mineral content. Xpr1‐deficient placentas show abnormal Pi exchange during gestation. Therefore, Xpr1 deficiency in the placenta disrupts placental‐fetal Pi homeostasis. We also discovered that the placentas of the Xpr1+/− and Xpr1−/− embryos are severely calcified. Mendelian inheritance statistics for offspring outcomes indicated that Xpr1‐deficient embryos are significantly reduced in late gestation. In addition, Xpr1−/− mice die perinatally and a small proportion of Xpr1+/− mice die neonatally. RNA sequence (RNA‐Seq) analysis of placental mRNA revealed that many of the transcripts are significantly differentially expressed due to Xpr1 deficiency and are linked to dysfunction of the placenta. This study is the first to reveal that XPR1 plays an important role in maintaining placental‐fetal Pi homeostasis, disruption of which causes severe placental calcification, delays normal placental function, and restricts fetal growth. © 2019 American Society for Bone and Mineral Research.

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“…However, it has been reported that in zebrafish - xpr1b , an orthologue of XPR1, is crucial for the differentiation of tissue-resident macrophages and microglia 107 . In mice, the full knockout of Xpr1 is embryonic lethal 108 , but the embryonic phenotype has not been characterized. Thus, further studies are needed to dissect the role of PFBC genes in microglial function.…”

Section: Discussionmentioning

confidence: 99%

Microglia control small vessel calcification via TREM2

Zarb

Nassiri

Utz

et al. 2019

Preprint

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23Microglia participate in CNS development and homeostasis and are often implicated in 24 modulating disease processes in the CNS. However, less is known about the role of microglia 25 in the biology of the neurovascular unit (NVU). In particular, data are scant on whether 26 microglia are involved in CNS vascular pathology. In this study, we use a mouse model of 27 primary familial brain calcification (PFBC) -Pdgfb ret/ret to investigate the role of microglia in 28 calcification of the NVU. We report that microglia enclosing vessel-calcifications, coined 29 calcification-associated microglia (CAM), display a distinct activation signature. 30Pharmacological ablation of microglia with the CSF1R inhibitor -PLX5622 leads to aggravated 31 vessel calcification. Additionally, depletion of microglia in wild-type and Pdgfb ret/ret mice 32 causes the development of bone protein (osteocalcin, osteopontin) containing axonal spheroids 33 in the white matter. Mechanistically, we show that microglia require functional TREM2 for 34 controlling vessel-associated calcification. In conclusion, our results demonstrate that 35 microglial activity in the setting of pathological vascular calcification is beneficial. In addition, 36we identify a new, previously unrecognized function of microglia in halting the expansion of 37 ectopic calcification. 38 39 2 injury results in microglial activation with the rapid development of processes that shield a 57 lesioned blood vessel section and phagocytose debris 2 . These findings support the important 58 role of microglia in vascular repair. 59Optimal functioning of the NVU, which mediates hyperaemia, is crucial for cerebral 60 perfusion 4 . Blood vessels play an integral role in brain development and provide a niche for 61 brain stem cells. In addition, cerebral vasculature senses the environment and communicates 62 changes to neural tissue, participates in glymphatic clearance, and controls immune quiescence 63 in the CNS [11][12][13][14][15] . Accordingly, dysfunction of the NVU accompanies or may even represent a 64 primary cause of many neurodegenerative diseases 4,16 . In the case of the primary familial brain 65 calcification (PFBC), bilateral basal ganglia calcification of blood vessels is a key diagnostic 66 criterion. The pathogenic mechanism points to a compromised NVU 17-20 . PFBC is a clinically 67 and genetically heterogenous disease caused by mutations in at least in five genes -MYORG, 68 PDGFB, PDGFRB, SLC20A2 and XPR1 21-25 . Of note, recent studies have estimated the 69 minimal prevalence of PFBC ranges from 4-6 p. 10,000, depending of the causative gene 70 mutation, thus suggesting that PFBC is not a rare disorder and is likely underdiagnosed 26,27 . In 71 addition, basal ganglia calcification is a common radiological finding, estimated in up to 20% 72 3 of patients undergoing CT imaging 28,29 . Although the effect of cerebral calcification on the 73 NVU and brain parenchyma is unknown, peripheral vascular calcification can lead to 74 cardiovascular morbidity and mortality...

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Renal Fanconi Syndrome and Hypophosphatemic Rickets in the Absence of Xenotropic and Polytropic Retroviral Receptor in the Nephron

Cited by 61 publications

References 11 publications

Memo1gene expression in kidney and bone is unaffected by dietary mineral load and calciotropic hormones

Memo1gene expression in kidney and bone is unaffected by dietary mineral load and calciotropic hormones

Murine Placental-Fetal Phosphate Dyshomeostasis Caused by an Xpr1 Deficiency Accelerates Placental Calcification and Restricts Fetal Growth in Late Gestation

Microglia control small vessel calcification via TREM2

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