ATP-sensitive potassium (KATP) channel openers diazoxide and nicorandil lower intraocular pressure by activating the Erk1/2 signaling pathway
ATP-sensitive potassium (KATP) channel openers diazoxide and nicorandil lower intraocular pressure by activating the Erk1/2 signaling pathway
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DOI：
10.1371/journal.pone.0179345
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发表时间：
2017-06-08
期刊：
影响因子：
3.7
通讯作者：
Fautsch, Michael P.
中科院分区：
文献类型：
--
作者：
Chowdhury, Uttio Roy;Bahler, Cindy K.;Fautsch, Michael P.
眼内压升高是青光眼（一种视神经退行性疾病）最普遍和唯一可治疗的风险因素。虽然有减缓疾病进展的治疗选择，但目前所有的治疗和手术治疗都有不必要的副作用或疗效有限，因此需要确定新的选择。我们实验室的先前报告已经确定了ATP敏感性钾通道（KATP）开放剂包括二氮嗪（DZ）和尼可地尔（NCD）的新型眼部扩张作用。在本研究中，我们评估了Erk 1/2信号通路在KATP通道开放剂介导的降低眼内压（IOP）中的作用。DZ和NCD处理的原代正常小梁网（NTM）细胞、人TM（分离自人眼前节的灌注培养物）和小鼠眼睛的蛋白质印迹分析显示，与载体处理的对照相比，Erk 1/2的磷酸化增加。U 0126消除了人眼前节中DZ和NCD介导的压力降低（p< 0.02）（DZ为n = 7，NCD为n = 4）（DZ + U 0126：-9.7 +/-11.5%，p = 0.11; NCD + U 0126：-0.1 +/-11.5%，p = 1.0）。相比之下，U 0126对拉坦前列腺素游离酸诱导的压力降低没有影响（-52.5 +/-6.8%，n = 4，p = 0.001）。在小鼠中，DZ和NCD降低IOP（DZ，14.9 +/-3.8%，NCD，16.9 +/-2.5%，n = 10，p< 0.001），但U 0126抑制了压力降低（DZ + U 0126，0.7 +/- 3.0%; NCD + U 0126，0.9 +/-2.2%，n = 10，p> 0.1）。DZ + U 0126和NCD + U 0126处理眼的透射电子显微镜照片的组织学评价显示，常规流出道的超微结构未观察到形态学变化。综上所述，结果表明Erk 1/2途径是KATP通道开放剂DZ和NCD降低IOP所必需的。
Elevated intraocular pressure is the most prevalent and only treatable risk factor for glaucoma, a degenerative disease of the optic nerve. While treatment options to slow disease progression are available, all current therapeutic and surgical treatments have unwanted side effects or limited efficacy, resulting in the need to identify new options. Previous reports from our laboratory have established a novel ocular hypotensive effect of ATP-sensitive potassium channel (KATP) openers including diazoxide (DZ) and nicorandil (NCD). In the current study, we evaluated the role of Erk1/2 signaling pathway in KATP channel opener mediated reduction of intraocular pressure (IOP). Western blot analysis of DZ and NCD treated primary normal trabecular meshwork (NTM) cells, human TM (isolated from perfusion cultures of human anterior segments) and mouse eyes showed increased phosphorylation of Erk1/2 when compared to vehicle treated controls. DZ and NCD mediated pressure reduction (p< 0.02) in human anterior segments (n = 7 for DZ, n = 4 for NCD) was abrogated by U0126 (DZ + U0126: -9.7 +/- 11.5%, p = 0.11; NCD + U0126: -0.1 +/- 11.5%, p = 1.0). In contrast, U0126 had no effect on latanoprostfree acid-induced pressure reduction (-52.5 +/- 6.8%, n = 4, p = 0.001). In mice, DZ and NCD reduced IOP (DZ, 14.9 +/- 3.8%, NCD, 16.9 +/- 2.5%, n = 10, p< 0.001), but the pressure reduction was inhibited by U0126 (DZ + U0126, 0.7 +/- 3.0%; NCD + U0126, 0.9 +/- 2.2%, n = 10, p> 0.1). Histologic evaluation of transmission electron micrographs from DZ + U0126 and NCD + U0126 treated eyes revealed no observable morphological changes in the ultrastructure of the conventional outflow pathway. Taken together, the results indicate that the Erk1/2 pathway is necessary for IOP reduction by KATP channel openers DZ and NCD.