Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
Neuroscience. 2010 Jul 28;168(4):1019-35. doi: 10.1016/j.neuroscience.2010.01.037. Epub 2010 Jan 28.
Although malfunction of spinal cord water channels (aquaporins, AQP) likely contributes to severe disturbances in ion/water homeostasis after spinal cord injury (SCI), their roles are still poorly understood. Here we report and discuss the potential significance of changes in the AQP4 expression in human SCI that generates glial fibrillary acidic protein (GFAP)-labeled astrocytes devoid of AQP4, and GFAP-labeled astroglia that overexpress AQP4. We used a rat model of contusion SCI to study observed changes in human SCI. AQP4-negative astrocytes are likely generated during the process of SCI-induced replacement of lost astrocytes, but their origin and role in SCI remains to be investigated. We found that AQP4-overexpression is likely triggered by hypoxia. Our transcriptional profiling of injured rat cords suggests that elevated AQP4-mediated water influx accompanies increased uptake of chloride and potassium ions which represents a protective astrocytic reaction to hypoxia. However, unbalanced water intake also results in astrocytic swelling that can contribute to motor impairment, but likely only in milder injuries. In severe rat SCI, a low abundance of AQP4-overexpressing astrocytes was found during the motor recovery phase. Our results suggest that severe rat contusion SCI is a better model to analyze AQP4 functions after SCI. We found that AQP4 increases in the chronic post-injury phase are associated with the development of pain-like behavior in SCI rats, while possible mechanisms underlying pain development may involve astrocytic swelling-induced glutamate release. In contrast, the formation and size of fluid-filled cavities occurring later after SCI does not appear to be affected by the extent of increased AQP4 levels. Therefore, the effect of therapeutic interventions targeting AQP4 will depend not only on the time interval after SCI or animal models, but also on the balance between protective role of increased AQP4 in hypoxia and deleterious effects of ongoing astrocytic swelling.
尽管脊髓水通道（水通道蛋白，AQP）的功能障碍可能导致脊髓损伤（SCI）后离子/水稳态严重紊乱，但它们的作用仍知之甚少。在这里，我们报告并讨论了 AQP4 表达变化在人类 SCI 中的潜在意义，这些变化导致胶质纤维酸性蛋白（GFAP）标记的缺乏 AQP4 的星形胶质细胞和过表达 AQP4 的 GFAP 标记的星形胶质细胞。我们使用大鼠挫伤 SCI 模型来研究人类 SCI 中观察到的变化。AQP4 阴性星形胶质细胞可能是在 SCI 诱导的丢失星形胶质细胞替代过程中产生的，但它们的起源和在 SCI 中的作用仍有待研究。我们发现 AQP4 的过表达可能是由缺氧触发的。我们对损伤大鼠脊髓的转录谱分析表明，AQP4 介导的水流入增加伴随着氯离子和钾离子的摄取增加，这代表了缺氧条件下的一种保护性星形胶质细胞反应。然而，不平衡的水摄入也会导致星形胶质细胞肿胀，从而导致运动障碍，但可能仅在轻度损伤中。在严重的大鼠 SCI 中，在运动恢复阶段发现 AQP4 过表达星形胶质细胞的丰度较低。我们的结果表明，严重的大鼠挫伤 SCI 是分析 SCI 后 AQP4 功能的更好模型。我们发现，AQP4 在慢性损伤后阶段的增加与 SCI 大鼠疼痛样行为的发展有关，而疼痛发展的可能机制可能涉及星形胶质细胞肿胀诱导的谷氨酸释放。相比之下，SCI 后较晚出现的液体积聚腔的形成和大小似乎不受 AQP4 水平增加程度的影响。因此，针对 AQP4 的治疗干预的效果不仅取决于 SCI 后或动物模型的时间间隔，还取决于 AQP4 在缺氧中的保护作用与持续的星形胶质细胞肿胀的有害作用之间的平衡。
