TRPV4拮抗作用在血管抑制素对血视网膜屏障通透性的调节作用中的双重作用：糖尿病环境有所作为。,Scientific Reports

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TRPV4拮抗作用在血管抑制素对血视网膜屏障通透性的调节作用中的双重作用：糖尿病环境有所作为。
Scientific Reports ( IF 3.8 ) Pub Date : 2017-Oct-12 , DOI: 10.1038/s41598-017-13621-8
David Arredondo Zamarripa , Ramsés Noguez Imm , Ana María Bautista Cortés , Osvaldo Vázquez Ruíz , Michela Bernardini , Alessandra Fiorio Pla , Dimitra Gkika , Natalia Prevarskaya , Fernando López-Casillas , Wolfgang Liedtke , Carmen Clapp , Stéphanie Thébault

糖尿病视网膜病变和其他慢性视网膜疾病中发生的血视网膜屏障（BRB）分解会导致血管源性水肿和神经组织损伤，从而导致视力丧失。血管抑制素是催乳素的N末端片段，可防止糖尿病期间BRB分解。他们调节某些瞬时受体电位（TRP）家族成员的表达，但它们在调节TRP香草样亚型4（TRPV4）中的作用仍然未知。TRPV4是参与屏障通透性的钙渗透通道，已显示该阻断作用可以预防和解决肺水肿。我们发现TRPV4在BRB的内皮和视网膜色素上皮（RPE）组件中表达，并且TRPV4选择性拮抗剂（RN-1734和GSK2193874）解决了糖尿病大鼠中的BRB分解。使用人RPE（ARPE-19）细胞单层和内皮细胞系统，我们进一步观察到（i）GSK2193874在糖尿病或高血糖模拟条件下似乎不通过血管抑制素对BRB和RPE通透性的调节做出贡献，但是（ii血管抑制素可以阻断TRPV4维持BRB和内皮通透性。我们的结果为糖尿病性视网膜病变的发病机理提供了重要见解，将进一步指导我们朝着合理指导的新疗法方向发展：可以提出选择性TRPV4阻断剂和血管抑制素的协同组合以减轻糖尿病引起的BRB分解。但是（ii）血管抑制素可以阻断TRPV4维持BRB和内皮通透性。我们的结果为糖尿病性视网膜病变的发病机理提供了重要见解，将进一步指导我们朝着合理指导的新疗法方向发展：可以提出选择性TRPV4阻断剂和血管抑制素的协同组合以减轻糖尿病引起的BRB分解。但是（ii）血管抑制素可以阻断TRPV4维持BRB和内皮通透性。我们的结果为糖尿病性视网膜病变的发病机理提供了重要见解，将进一步指导我们朝着合理指导的新疗法方向发展：可以提出选择性TRPV4阻断剂和血管抑制素的协同组合以减轻糖尿病引起的BRB分解。

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Dual contribution of TRPV4 antagonism in the regulatory effect of vasoinhibins on blood-retinal barrier permeability: diabetic milieu makes a difference.

Breakdown of the blood-retinal barrier (BRB), as occurs in diabetic retinopathy and other chronic retinal diseases, results in vasogenic edema and neural tissue damage, causing vision loss. Vasoinhibins are N-terminal fragments of prolactin that prevent BRB breakdown during diabetes. They modulate the expression of some transient receptor potential (TRP) family members, yet their role in regulating the TRP vanilloid subtype 4 (TRPV4) remains unknown. TRPV4 is a calcium-permeable channel involved in barrier permeability, which blockade has been shown to prevent and resolve pulmonary edema. We found TRPV4 expression in the endothelium and retinal pigment epithelium (RPE) components of the BRB, and that TRPV4-selective antagonists (RN-1734 and GSK2193874) resolve BRB breakdown in diabetic rats. Using human RPE (ARPE-19) cell monolayers and endothelial cell systems, we further observed that (i) GSK2193874 does not seem to contribute to the regulation of BRB and RPE permeability by vasoinhibins under diabetic or hyperglycemic-mimicking conditions, but that (ii) vasoinhibins can block TRPV4 to maintain BRB and endothelial permeability. Our results provide important insights into the pathogenesis of diabetic retinopathy that will further guide us toward rationally-guided new therapies: synergistic combination of selective TRPV4 blockers and vasoinhibins can be proposed to mitigate diabetes-evoked BRB breakdown.

更新日期：2017-10-12

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