Bestrophin-2 is involved in the generation of intraocular pressure
Bestrophin-2 is involved in the generation of intraocular pressure
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DOI：
10.1167/iovs.07-1338
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发表时间：
2008-04-01
影响因子：
4.4
通讯作者：
Marmorstein, Alan D.
中科院分区：
文献类型：
--
作者：
Bakall, Benjamin;McLaughlin, Precious;Marmorstein, Alan D.
目的。已经证明了BestRophin蛋白质家族可以产生或调节Ca2+激活的Cl-电导。 Bestrophin-1（Best1）的突变引起了几种盲目的眼部疾病，但对其他Bestrophin家族成员知之甚少。这项研究涉及小鼠中最佳2基因的破坏。用RT-PCR，X-GAL染色和免疫组织化学检查了BESTROPHIN-2（BEST2）的表达曲线（BEST2），通过将外显子1、2和外显子3的一部分替换为外显子3和部分的部分来破坏小鼠Best2基因。眼内压（IOP）通过前室插管测量。小鼠组织的RT-PCR揭示了眼睛，结肠，鼻上皮，气管，脑，肺和肾脏中最佳2 mRNA。 X-gal染色，在未浸润上皮（NPE）中证实在结肠上皮和眼中的表达。最好的2在RPE细胞中未表达。最佳2蛋白仅在NPE和结肠上皮观察到。最好的2对老鼠没有明显的有害影响。但是，发现最佳2（p <0.02）的最佳2（ - / - ）小鼠相对于Best2（+/+）和Best2（+/-）同窝倍数显着减少IOP。最好的2（ - / - ）和Best2（+/-）小鼠对碳酸酐酶抑制剂Brinzolamide的反应要好于其最好的2（+/+）同elmates，尽管β受体阻滞剂Timolol Timolol将IOP带到了相同的水平，无论基因型如何。 Best2通过调节水性幽默的形成在IOP的产生中发挥作用，而对BEST2功能的抑制代表了调节青光眼患者IOP的有吸引力的新途径。
PURPOSE. The bestrophin family of proteins has been demonstrated to generate or regulate Ca2+-activated Cl- conductances. Mutations in bestrophin-1 (Best1) cause several blinding eye diseases, but little is known about other bestrophin family members. This study involved disruption of the Best2 gene in mice.METHODS. The mouse Best2 gene was disrupted by replacing exons 1, 2, and part of exon 3 with a Lac Z. The expression profile of Bestrophin-2 ( Best2) was examined using RT-PCR, X-gal staining, and immunohistochemistry. Intraocular pressure ( IOP) was measured by anterior chamber cannulation.RESULTS. RT-PCR of mouse tissues revealed Best2 mRNA in eye, colon, nasal epithelia, trachea, brain, lung, and kidney. X-gal staining, confirmed expression in colon epithelia and in the eye, in the nonpigmented epithelia ( NPE). Best2 was not expressed in RPE cells. Best2 protein was observed only in NPE and colon epithelia. The absence of Best2 had no obvious deleterious effect on the mice. However, the Best2(-/-) mice were found to have significantly ( P < 0.02) diminished IOP with respect to the Best2(+/+) and Best2(+/-) littermates. The Best2(-/-) and Best2(+/-) mice responded better to the carbonic anhydrase inhibitor brinzolamide than did their Best2(+/+) littermates, although the beta-blocker timolol brought IOP to the same level, regardless of genotype.CONCLUSIONS. Best2 plays a role in the generation of IOP by regulating formation of aqueous humor, and inhibition of Best2 function represents an attractive new avenue for regulating IOP in individuals with glaucoma.