Region-specific changes in aquaporin 4 induced by hyperglycemia underlie the differences in cell swelling in the cortex and striatum after cerebral ischemia-reperfusion
Introduction
Diabetes and stroke are both major global diseases that seriously threaten human health. A large number of studies have confirmed that diabetes can aggravate the injury in ischemic stroke. In comparison with non-diabetic patients, diabetic patients are 2–3 times more likely to have stroke, and the mortality and severity of sequelae in diabetes patients are significantly higher than those in normoglycemic individuals [8,12]. Animal experiments have also shown that hyperglycemia can aggravate the cerebral infarction volume and neuronal apoptosis in a cerebral ischemia model and aggravate neurological impairment [19,32]. However, the specific mechanisms underlying the aggravation of cerebral ischemic injury by diabetes require elucidation.
Hyperglycemia can significantly increase the degree of brain edema in middle cerebral artery occlusion (MCAO) rats [34]. Brain edema is one of the earliest pathological changes in ischemic stroke, and its progression can lead to apoptosis or necrosis [10]. The cerebral hernia caused by severe brain edema is the main cause of death in patients [7]. Previous studies on brain edema mainly focused on the cerebral cortex, partly because damage to the cerebral cortex was closely related to a variety of neurological defects after ischemia. However, the striatum may be more likely to swell than the cortex after cerebral ischemia, and the edema in the striatum is less likely to subside with drug treatment [18]. A recent study reported neurogenesis in the striatum to promote the recovery of neurological function after cerebral ischemia, which is not found in the cerebral cortex [25]. According to another clinical study, reduced volumes in the subcortical striatum, but not in the cortex, are associated with cognitive impairment in diabetes [29]. These findings suggest that a thorough exploration of the differences and mechanisms associated with the effects of hyperglycemia on cortical and striatal edema is of great significance for further understanding the mechanism and clinical treatment of cerebral ischemic injury aggravated by diabetes.
Aquaporin 4 (AQP4) is the most abundant member of the aquaporin family in the brain. It is mainly distributed in astrocytes and ependymal cells, and it plays an important role in the formation and regression of brain edema [3]. AQP4 is polarized in astrocytes, that is, it is mainly distributed in the membrane of the astrocytic endfeet surrounding the vascular region [23]. In some pathological conditions, this polarity disappears, resulting in dysfunction of water transport. AQP4 upregulation after cerebral ischemia is generally believed to promote the formation of brain edema. The transcriptional and translational levels of AQP4 in a permanent MCAO model were upregulated after 30 min of ischemia [15]. In a transient cerebral ischemia rat model, AQP4 expression in the penumbra began to increase at 24 h after ischemia and returned to normal at least 72 h and 28 d after ischemia, which was consistent with the degree of brain edema shown on MRI [2].
AQP4 knockdown can reduce the degree of brain edema after 24 h of ischemia [22], and siRNA-based interference in AQP4 expression can reduce neuronal edema after 6 h of MCAO [13]. However, a recent global cerebral ischemia model showed that the AQP4 expression did not significantly change within 48 h after ischemia [1]. These differences in the findings may be related to the different models used or the different brain regions observed in these studies, since gene expression and function of astrocytes in the cerebral cortex and striatum have been reported to show significant heterogeneity [6,24]. A new single-cell sequencing study found that even within the same brain region, the expression of genes and signal pathways in astrocytes were almost completely different in different environments [33]. Thus, we speculate that hyperglycemia has different effects on AQP4 expression and distribution in astrocytes in the cortex and striatum, resulting in regional differences in the extent of brain edema.
To confirm this hypothesis, we established a cerebral ischemia-reperfusion (I/R) rat model with diabetes by intraperitoneal injection of streptozocin (STZ) and MCAO, and observed the differences in the AQP4 expression and distribution and brain edema between the cortical and striatal penumbra by morphological methods. These results will improve our understanding of the mechanism by which diabetes aggravates cerebral ischemic injury and facilitate the development of targeted treatment strategies.
Section snippets
Animals
Sixty-eight male 8-week-old Sprague-Dawley rats weighing approximately 200 g were selected and provided by the Experimental Animal Center of Ningxia Medical University. The animals were reared in a specific pathogen-free environment with a light/dark cycle of 12 h and free access to water and food. The animal procedures were approved by the Ethics Committee of Ningxia Medical University. After intraperitoneal injection of STZ or citrate buffer, the animals were divided into two groups:
Hyperglycemia aggravates cerebral infarction volume and neurological impairment after cerebral I/R
Within four weeks after intraperitoneal injection of STZ, the food intake and urine volume of rats in the HG increased. The body weight of rats in the NG increased gradually every week, with an average increase of about 43.3 g per week, while it showed no increase or decrease in the HG (Fig. 1A). The blood glucose concentration fluctuated, but remained greater than 16.7 mmol/L (Fig. 1B).
We used LSCI to detect the cerebral blood flow during MCAO surgery to assess the success of the model. As
Discussion
In the present study, we demonstrated that hyperglycemia aggravates the cerebral edema induced by I/R in both the cortex and striatum, but the effect on the latter is more obvious than that on the former, characterized by a more significant increase in the number of swollen cells in the acute injury period and a slower regression of edema in the recovery period. At the same time, we observed significant regional heterogeneity in the effect of hyperglycemia on the expression and distribution of
CRediT authorship contribution statement
Yong-Zhen Guo: Data curation, Writing - original draft, Software. Yan-Mei Ma: Data curation, Writing - original draft, Resources. Xiao-Peng Zhang: Visualization, Investigation. Ling-Di Dong: Supervision, Software. Li Jing: Conceptualization, Funding acquisition. Jian-Zhong Zhang: Conceptualization, Methodology, Writing - review & editing.
Declaration of Competing Interest
The authors declare no conflicts of interest.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (31960177 to LJ, 31780280 to JZZ), and the Natural Science Foundation of Ningxia (XT2017027 to YMM)
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These authors contributed equally to this work.