Abstract
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% O2); or (3) intermittent hypoxia (IH) consisting of 50% O2 with brief, clustered episodes of 12% O2 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.
Highlights
Retinopathy of prematurity (ROP) has become one of the leading causes of childhood blindness world-wide, with increases in preterm births [1]
Phase 2 occurs during recovery from hyperoxia, which results in vaso-proliferation, partly as a result of elevation of vascular endothelial growth factor (VEGF) and other growth factors, such as insulin-like growth factor (IGF)-I [6]
These findings suggest that AQP1 and AQP4 may play a key role in the restorative process following hyperoxia/hypoxia
Summary
Retinopathy of prematurity (ROP) has become one of the leading causes of childhood blindness world-wide, with increases in preterm births [1]. Studies showed even when oxygen is regulated, ROP can still occur in the smallest and youngest preterm infants [3,4,5]. Phase 1 occurs during hyperoxia, which results in suppression of retinal vascularization or in vaso-obliteration. This is due to the suppressive effect of oxygen on vascular endothelial growth factor (VEGF), the most potent mitogen specific to vascular endothelial cells. Current treatments for severe ROP include laser, preferable to cryotherapy, with 75% success rates [14,15], and targeting VEGF despite long-term adverse outcomes [16]. The use of anti-VEGF therapies in preterm infants at a critical stage of development may have severe long-term adverse effects [17]
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