Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA.
Department of Ophthalmology, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA.
Int J Mol Sci. 2020 Feb 2;21(3):987. doi: 10.3390/ijms21030987.
Aquaporins (AQPs) are involved in hypoxia-induced angiogenesis and retinal damage. Bumetanide is a diuretic agent, Na/K/Cl cotransporter (NKCC1), and AQP 1-4 inhibitor. We tested the hypothesis that early postnatal treatment with bumetanide suppresses biomarkers of angiogenesis and decreases severe retinopathy oxygen-induced retinopathy (OIR). Neonatal rats were exposed at birth (P0) to either (1) room air (RA); (2) hyperoxia (50% O); or (3) intermittent hypoxia (IH) consisting of 50% O with brief, clustered episodes of 12% O from P0 to postnatal day 14 (P14), during which they were treated intraperitoneally (IP) with bumetanide (0.1 mg/kg/day) or an equivalent volume of saline, on P0-P2. Pups were examined at P14 or allowed to recover in RA from P14-P21. Retinal angiogenesis, morphometry, pathology, AQPs, and angiogenesis biomarkers were determined at P14 and P21. Bumetanide reduced vascular abnormalities associated with severe OIR. This was associated with reductions in AQP-4 and VEGF. Bumetanide suppressed sVEGFR-1 in the serum and vitreous fluid, but levels were increased in the ocular tissues during recovery. Similar responses were noted for IGF-I. In this model, early systemic bumetanide administration reduces severe OIR, the benefits of which appear to be mediated via suppression of AQP-4 and VEGF. Further studies are needed to determine whether bumetanide at the right doses may be considered a potential pharmacologic agent to treat retinal neovascularization.
水通道蛋白（AQP）参与缺氧诱导的血管生成和视网膜损伤。布美他尼是一种利尿剂、钠/钾/氯共转运体（NKCC1）和 AQP1-4 抑制剂。我们检验了以下假说，即在新生后早期用布美他尼治疗可抑制血管生成生物标志物并减少严重视网膜病变氧诱导视网膜病变（OIR）。新生大鼠在出生时（P0）暴露于以下条件：（1）空气（RA）；（2）高氧（50% O）；或（3）间歇性低氧（IH），包括从 P0 到 P14 每天 50% O 与短暂、成簇的 12% O 相结合，在此期间，它们接受腹膜内（IP）注射布美他尼（0.1mg/kg/天）或等体积生理盐水，在 P0-P2 期间。P0-P21 期间，在 P14 或在 RA 中恢复时检查幼鼠。在 P14 和 P21 时确定视网膜血管生成、形态计量学、病理学、AQP 和血管生成生物标志物。布美他尼减少了与严重 OIR 相关的血管异常。这与 AQP-4 和 VEGF 的减少有关。布美他尼抑制了血清和玻璃体中的 sVEGFR-1，但在恢复期间眼组织中的水平增加。IGF-I 也有类似的反应。在该模型中，早期全身布美他尼给药可减少严重 OIR，其益处似乎是通过抑制 AQP-4 和 VEGF 来介导的。需要进一步的研究来确定在正确剂量下布美他尼是否可以被认为是治疗视网膜新生血管的潜在药物。
