钙感受体（CaSR）调节眼表氯离子转运，抑制钙感受体可促进眼表水合。

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface Pub Date : 2024-06-11 DOI:10.1016/j.jtos.2024.06.002

Neel D. Pasricha , Ethan S. Lindgren , Rongshan Yan , Yien-Ming Kuo , Matilda Chan , Alan S. Verkman , Tifany Chu , Pattareeya Yottasan , Livia de Souza Goncalves , Onur Cil

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引用次数: 0

摘要

目的：眼表水合对眼睛健康至关重要，其受损会导致干眼症。细胞外钙感应受体（CaSR）是表达囊性纤维化跨膜传导调节器（CFTR）Cl- 通道的上皮细胞中离子转运的调节器。CFTR也是眼表上皮细胞的主要离子通道，但CaSR在眼表的作用尚未得到深入研究。本研究旨在探讨 CaSR 在眼表的表达和功能作用：方法：对小鼠和人的角膜和结膜进行 CaSR 免疫染色。方法：在小鼠和人的角膜和结膜上进行 CaSR 免疫染色，在局部应用西那卡西酮（CaSR 激活剂）和 NPS-2143（CaSR 抑制剂）的小鼠中进行眼表电位差（OSPD）和泪液容量测量：结果：CaSR 在小鼠和人类的角膜和结膜上皮中均有表达。局部给药 CaSR 激活剂 cinacalcet 可抑制 cAMP 激动剂 forskolin 诱导的 Cl- 分泌和 CFTR 活性达 90%。CaSR抑制剂NPS-2143可刺激小鼠眼表CFTR介导的Cl-分泌，之后cAMP激动剂福斯克林对分泌的额外影响微乎其微。单剂量 NPS-2143 治疗（滴眼液）可使小鼠的泪液量比药物治疗增加 60%。单次给药后，NPS-2143 对泪液量的影响至少持续 8 小时：结论：CaSR 是眼表离子转运的关键调节因子，抑制 CaSR 可促进眼表 Cl- 和泪液分泌。如果在干眼症模型中发现它们有效，CaSR 抑制剂（目前正在临床开发中）就有可能被重新用作干眼症的新型分泌治疗。

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Calcium-sensing receptor (CaSR) modulates ocular surface chloride transport and its inhibition promotes ocular surface hydration

Purpose

Ocular surface hydration is critical for eye health and its impairment can lead to dry eye disease. Extracellular calcium-sensing receptor (CaSR) is regulator of ion transport in epithelial cells expressing cystic fibrosis transmembrane conductance regulator (CFTR) Cl⁻ channel. CFTR is also a major ion channel in ocular surface epithelia, however the roles of CaSR in ocular surface are not well studied. This study aims to investigate expression and functional roles of CaSR in ocular surface.

Methods

CaSR immunostaining was performed in mouse and human cornea and conjunctiva. Ocular surface potential difference (OSPD) and tear fluid volume measurements were performed in mice with topically applied cinacalcet (CaSR activator) and NPS-2143 (CaSR inhibitor).

Results

CaSR is expressed in corneal and conjunctival epithelia of mice and humans. Topically administered CaSR activator cinacalcet inhibits cAMP agonist forskolin-induced Cl⁻ secretion and CFTR activity up to 90 %. CaSR inhibitor NPS-2143 stimulates CFTR-mediated Cl⁻ secretion in mouse ocular surface, after which cAMP agonist forskolin had minimal additional secretory effects. Single dose NPS-2143 treatment (as an eye drop) increases tear fluid volume in mice by ∼60 % compared to vehicle treatment. NPS-2143 effect on tear volume lasts at least 8 h after single dose.

Conclusions

CaSR is a key regulator of ocular surface ion transport and CaSR inhibition promotes Cl⁻ and tear secretion in the ocular surface. If they are found to be effective in in dry eye models, CaSR inhibitors (currently in clinical development) can potentially be repurposed as novel prosecretory treatments for dry eye disease.

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来源期刊

Ocular Surface 医学-眼科学

CiteScore

11.60

自引率

14.10%

发文量

审稿时长

39 days

期刊介绍： The Ocular Surface, a quarterly, a peer-reviewed journal, is an authoritative resource that integrates and interprets major findings in diverse fields related to the ocular surface, including ophthalmology, optometry, genetics, molecular biology, pharmacology, immunology, infectious disease, and epidemiology. Its critical review articles cover the most current knowledge on medical and surgical management of ocular surface pathology, new understandings of ocular surface physiology, the meaning of recent discoveries on how the ocular surface responds to injury and disease, and updates on drug and device development. The journal also publishes select original research reports and articles describing cutting-edge techniques and technology in the field. Benefits to authors We also provide many author benefits, such as free PDFs, a liberal copyright policy, special discounts on Elsevier publications and much more. Please click here for more information on our author services. Please see our Guide for Authors for information on article submission. If you require any further information or help, please visit our Support Center