Shortened primary cilium length and dysregulated Sonic hedgehog signaling in Niemann-Pick C1 disease

Canterini, Sonia; Dragotto, Jessica; Dardis, Andrea; Zampieri, Stefania; Stefano, Maria Egle De; Mangia, Franco; Erickson, Robert P.; Fiorenza, Maria Teresa

doi:10.1093/hmg/ddx118

Cited by 55 publications

(40 citation statements)

References 65 publications

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“…In parallel with the increased intracellular cholesterol, we found that deletion of ABCA1 can shorten the primary cilia of principal cells. This is consistent with previous studies showing that cholesterol modulates the length of cilia (Canterini et al, ; Formichi et al, ). The cilia function as a sensor of distal nephron flow (Praetorius & Spring, ) to control ATP release from the principal cells (Hovater et al, ).…”

Section: Discussionsupporting

confidence: 94%

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Lovastatin attenuates hypertension induced by renal tubule‐specific knockout of ATP‐binding cassette transporter A1, by inhibiting epithelial sodium channels

Chen

et al. 2019

British J Pharmacology

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Background and Purpose We have shown that cholesterol is synthesized in the principal cells of renal cortical collecting ducts (CCD) and stimulates the epithelial sodium channels (ENaC). Here we have determined whether lovastatin, a cholesterol synthesis inhibitor, can antagonize the hypertension induced by activated ENaC, following deletion of the cholesterol transporter (ATP‐binding cassette transporter A1; ABCA1). Experimental Approach We selectively deleted ABCA1 in the principal cells of mouse CCD and used the cell‐attached patch‐clamp technique to record ENaC activity. Western blot and immunofluorescence staining were used to evaluate protein expression levels. Systolic BP was measured with the tail‐cuff method. Key Results Specific deletion of ABCA1 elevated BP and ENaC single‐channel activity in the principal cells of CCD in mice. These effects were antagonized by lovastatin. ABCA1 deletion elevated intracellular cholesterol levels, which was accompanied by elevated ROS, increased expression of serum/glucocorticoid regulated kinase 1 (Sgk1), phosphorylated neural precursor cell‐expressed developmentally down‐regulated protein 4‐2 (Nedd4‐2) and furin, along with shorten the primary cilium, and reduced ATP levels in urine. Conclusions and Implications These data suggest that specific deletion of ABCA1 in principal cells increases BP by stimulating ENaC channels via a cholesterol‐dependent pathway which induces several secondary responses associated with oxidative stress, activated Sgk1/Nedd4‐2, increased furin expression, and reduced cilium‐mediated release of ATP. As ABCA1 can be blocked by cyclosporine A, these results suggest further investigation of the possible use of statins to treat CsA‐induced hypertension.

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Section: Discussionsupporting

confidence: 94%

supporting

confidence: 94%

Lovastatin attenuates hypertension induced by renal tubule‐specific knockout of ATP‐binding cassette transporter A1, by inhibiting epithelial sodium channels

Chen

et al. 2019

British J Pharmacology

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“…Thus, an imbalance in cholesterol homeostasis resulting from reduced NPC1 protein could have subtle effects throughout development. In support of this, abnormal expression and localization of SHH and its receptor Patched has been shown in the cerebellum of Npc1 mutant mice at P14 as well as in NPC1 patient-derived fibroblasts [63,64]. These data along with other studies highlighting the importance of cholesterol for SHH function in the developing cerebellum suggest that important connections may exist between NPC1 and SHH signaling pathways [58,65,66].…”

Section: Discussionsupporting

confidence: 60%

NPC1 Deficiency in Mice is Associated with Fetal Growth Restriction, Neonatal Lethality and Abnormal Lung Pathology

Rodriguez-Gil

Watkins‐Chow

Baxter

et al. 2019

JCM

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The rare lysosomal storage disorder Niemann-Pick disease type C1 (NPC1) arises from mutation of NPC1, which encodes a lysosomal transmembrane protein essential for normal transport and trafficking of cholesterol and sphingolipids. NPC1 is highly heterogeneous in both clinical phenotypes and age of onset. Previous studies have reported sub-Mendelian survival rates for mice homozygous for various Npc1 mutant alleles but have not studied the potential mechanisms underlying this phenotype. We performed the first developmental analysis of a Npc1 mouse model, Npc1 em1Pav , and discovered significant fetal growth restriction in homozygous mutants beginning at E16.5. Npc1 em1Pav/em1Pav mice also exhibited cyanosis, increased respiratory effort, and over 50% lethality at birth. Analysis of neonatal lung tissues revealed lipid accumulation, notable abnormalities in surfactant, and enlarged alveolar macrophages, suggesting that lung abnormalities may be associated with neonatal lethality in Npc1 em1Pav/em1Pav mice. The phenotypic severity of the Npc1 em1Pav model facilitated this first analysis of perinatal lethality and lung pathology in an NPC1 model organism, and this model may serve as a useful resource for developing treatments for respiratory complications seen in NPC1 patients.

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“…5A). Recent studies suggest that elevated intracellular Cho can shorten the primary cilium [40,41]. Since it is known that the primary cilia control the release of ATP [42] and that ATP strongly inhibits ENaC [43,44], it would be interesting to explore whether Cho can also alter ENaC activity by modulating the length of cilia.…”

Section: Discussionmentioning

confidence: 99%

Depletion of Cholesterol Reduces ENaC Activity by Decreasing Phosphatidylinositol-4,5-Bisphosphate in Microvilli

Zhai

Liu

Wei

et al. 2018

Cell Physiol Biochem

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Background/Aims: The epithelial sodium channel (ENaC) in cortical collecting duct (CCD) principal cells plays a critical role in regulating systemic blood pressure. We have previously shown that cholesterol (Cho) in the apical cell membrane regulates ENaC; however, the underlying mechanism remains unclear. Methods: Patch-clamp technique and confocal microscopy were used to evaluate ENaC activity and density. Results: Here we show that extraction of membrane Cho with methyl-β-cyclodextrin (MβCD) significantly reduced amiloride-sensitive current and ENaC single-channel activity. The effects were reproduced by inhibition of Cho synthesis in the cells with lovastatin. We have previously shown that phosphatidylinositol-4,5-bisphosphate (PIP₂), an ENaC activator, is predominantly located in the microvilli, a specialized apical membrane domain. Here, our confocal microscopy data show that α-ENaC was co-localized with PIP₂ in the microvilli and that Cho was also co-localized with PIP₂ in the microvilli. Either extraction of Cho with MβCD or inhibition of Cho synthesis with lovastatin consistently reduced the levels of Cho, PIP₂, and ENaC in the microvilli. Conclusions: Since PIP₂ can directly stimulate ENaC and also affect ENaC trafficking, these data suggest that depletion of Cho reduces ENaC apical density and activity at least in part by decreasing PIP₂ in the microvilli.

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Shortened primary cilium length and dysregulated Sonic hedgehog signaling in Niemann-Pick C1 disease

Cited by 55 publications

References 65 publications

Lovastatin attenuates hypertension induced by renal tubule‐specific knockout of ATP‐binding cassette transporter A1, by inhibiting epithelial sodium channels

Lovastatin attenuates hypertension induced by renal tubule‐specific knockout of ATP‐binding cassette transporter A1, by inhibiting epithelial sodium channels

NPC1 Deficiency in Mice is Associated with Fetal Growth Restriction, Neonatal Lethality and Abnormal Lung Pathology

Depletion of Cholesterol Reduces ENaC Activity by Decreasing Phosphatidylinositol-4,5-Bisphosphate in Microvilli

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