Ectodysplasin A regulates epithelial barrier function through sonic hedgehog signalling pathway

Li, Sanming; Zhou, Jing; Zhang, Liying; Li, Juan; Yu, Jingwen; Ning, Ke; Qu, Yangluowa; He, Hui; Chen, Yongxiong; Reinach, Peter S.; Liu, Chia-Yang; Liu, Zuguo; Li, Wei

doi:10.1111/jcmm.13311

Cited by 17 publications

(14 citation statements)

References 41 publications

(52 reference statements)

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“…EDA is a cytokine and part of the tumor necrosis factor family that functions in ectodermal organ development. In adulthood it is expressed in the kidney, and it functions to promote epithelial barrier function ( 52 ). EDA was reported to be significantly lower in peripheral blood mononuclear cells of CKD and end-stage renal disease subjects ( 53 ).…”

Section: Discussionmentioning

confidence: 99%

Fluid-electrolyte homeostasis requires histone deacetylase function

Hyndman¹,

Speed²,

Mendoza³

et al. 2020

JCI Insight

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Histone deacetylase (HDAC) enzymes regulate transcription through epigenetic modification of chromatin structure, but their specific functions in the kidney remain elusive. We discovered that the human kidney expresses class I HDACs. Kidney medulla-specific inhibition of class I HDACs in the rat during high-salt feeding results in hypertension, polyuria, hypokalemia, and nitric oxide deficiency. Three new inducible murine models were used to determine that HDAC1 and HDAC2 in the kidney epithelium are necessary for maintaining epithelial integrity and maintaining fluid-electrolyte balance during increased dietary sodium intake. Moreover, single-nucleus RNA-sequencing determined that epithelial HDAC1 and HDAC2 are necessary for expression of many sodium or water transporters and channels. In performing a systematic review and meta-analysis of serious adverse events associated with clinical HDAC inhibitor use, we found that HDAC inhibitors increased the odds ratio of experiencing fluid-electrolyte disorders, such as hypokalemia. This study provides insight on the mechanisms of potential serious adverse events with HDAC inhibitors, which may be fatal to critically ill patients. In conclusion, kidney tubular HDACs provide a link between the environment, such as consumption of high-salt diets, and regulation of homeostatic mechanisms to remain in fluid-electrolyte balance.

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Section: Discussionmentioning

confidence: 99%

Fluid-electrolyte homeostasis requires histone deacetylase function

Hyndman¹,

Speed²,

Mendoza³

et al. 2020

JCI Insight

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“…We recently reported that corneal epithelium is in an active wound-healing process 18 h after abrasion (Kalha et al, 2018b). Moreover, it was shown that Eda −/− animals present high corneal dystrophy, along with impaired corneal epithelium barrier function and delayed cornea wound healing (Li et al, 2018(Li et al, , 2017Wang et al, 2016). Our Eda −/− mouse strain did not exhibit corneal dystrophy in young animals (13 wo), but an epithelial thinning in old ones (52-64 wo) (Fig.…”

Section: Eda Loss Of Function Results In Impaired Lg Maturationmentioning

confidence: 53%

Ectodysplasin-A signaling is a key integrator in the lacrimal gland–cornea feedback loop

et al. 2019

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A lack of ectodysplasin-A (Eda) signaling leads to dry eye symptoms, which have so far only been associated with altered Meibomian glands. Here, we used loss-of-function (Eda −/−) mutant mice to unravel the impact of Eda signaling on lacrimal gland formation, maturation and subsequent physiological function. Our study demonstrates that Eda activity is dispensable during lacrimal gland embryonic development. However, using a transcriptomic approach, we show that the Eda pathway is necessary for proper cell terminal differentiation in lacrimal gland epithelium and correlated with modified expression of secreted factors commonly found in the tear film. Finally, we discovered that lacrimal glands present a bilateral reduction of Eda signaling activity in response to unilateral corneal injury. This observation hints towards a role for the Eda pathway in controlling the switch from basal to reflex tears, to support corneal wound healing. Collectively, our data suggest a crucial implication of Eda signaling in the cornea-lacrimal gland feedback loop, both in physiological and pathophysiological conditions. Our findings demonstrate that Eda downstream targets could help alleviate dry eye symptoms.

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“…The Eda gene regulates the morphogenesis of various ectodermal structures such as hair, teeth, nails, and exocrine glands, and when mutated, is responsible for X-linked hypohidrotic ectodermal dysplasia in humans. In Eda mutant Tabby mice, tight-junction proteins such as Zonula Occludens-1 (ZO-1) and Claudin-1 were dramatically downregulated, resulting in epithelial barrier dysfunction in various tissues including the cornea [ 53 ]. Furthermore, it was shown that EDA promotes corneal epithelial barrier homeostasis via the activation of Hedgehog signaling, which results in an increased production of ZO-1 and claudin-1 [ 53 ].…”

Section: Current Evidence Of Hedgehog Pathway Involvement In Physiolo...mentioning

confidence: 99%

Shhedding New Light on the Role of Hedgehog Signaling in Corneal Wound Healing

Zhang

Mélik-Parsadaniantz

Baudouin

et al. 2022

IJMS

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The cornea, an anterior ocular tissue that notably serves to protect the eye from external insults and refract light, requires constant epithelium renewal and efficient healing following injury to maintain ocular homeostasis. Although several key cell populations and molecular pathways implicated in corneal wound healing have already been thoroughly investigated, insufficient/impaired or excessive corneal wound healing remains a major clinical issue in ophthalmology, and new avenues of research are still needed to further improve corneal wound healing. Because of its implication in numerous cellular/tissular homeostatic processes and oxidative stress, there is growing evidence of the role of Hedgehog signaling pathway in physiological and pathological corneal wound healing. Reviewing current scientific evidence, Hedgehog signaling and its effectors participate in corneal wound healing mainly at the level of the corneal and limbal epithelium, where Sonic Hedgehog-mediated signaling promotes limbal stem cell proliferation and corneal epithelial cell proliferation and migration following corneal injury. Hedgehog signaling could also participate in corneal epithelial barrier homeostasis and in pathological corneal healing such as corneal injury-related neovascularization. By gaining a better understanding of the role of this double-edged sword in physiological and pathological corneal wound healing, fascinating new research avenues and therapeutic strategies will undoubtedly emerge.

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Ectodysplasin A regulates epithelial barrier function through sonic hedgehog signalling pathway

Cited by 17 publications

References 41 publications

Fluid-electrolyte homeostasis requires histone deacetylase function

Fluid-electrolyte homeostasis requires histone deacetylase function

Ectodysplasin-A signaling is a key integrator in the lacrimal gland–cornea feedback loop

Shhedding New Light on the Role of Hedgehog Signaling in Corneal Wound Healing

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