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Aquaporin 4 (AQP4) is a protein involved in the permeability of water. The AQP4 gene is located at the junction of human chromosome 18q11.2 and q12.1 and contains four exons. AQP4 is mainly distributed in supporting cells such as astrocytes, choroid plexus epithelial cells and ependymal epithelial cells in the central nervous system. AQP4 is abundantly expressed in astrocyte foot processes, glial conjunctiva, pia mater and chamber. The membrane is in the interstitial space of its underlying astrocytes. It has not been found to be expressed in excitatory cells. Gundersen et al. found that AQP4 is polarly distributed on astrocyte foot processes, and anchoring proteins and cell surrounding environment play a role in this distribution. Therefore, it can be inferred that it is related to the water balance of the central system by the distribution and expression characteristics of AQP4. A large number of studies have shown that AQP4 is not only closely related to the occurrence and development of cerebral edema but also participates in the pathological process of various neurological diseases, which is of great significance for the diagnosis and treatment of clinical nervous system diseases.
Inwardly rectifying K+ channel (Kir4.1) is a membrane of the central nervous system. Studies have shown that AQP4 and Kir4.1 have a co-coupled relationship in structure and function. The C-terminus of both is anchored to the cell membrane of glial cells by the PDZ domain of α-syntrophin. Changes in AQP4 expression can affect the movement of water molecules inside and outside the cell, which in turn leads to changes in potassium ion permeability in Kir4.1, and corresponding potential changes occur. Under pathological conditions, the expression of AQP4 was significantly increased in the hippocampus of patients with temporal lobe epilepsy, while that of Kir4.1 was down-regulated. Potassium ion balance is disrupted, and the anchoring protein complex of AQP4 and Kir4.1 is impaired. This suggests that both may participate in the pathological process of epilepsy through the functional coupling.
AQP4 and Brain Edema
A large number of studies have shown that elevated AQP4 expression is the main cause of brain edema caused by traumatic brain injury. Pizzo et al. found that AQP4 can effectively assess the severity of cerebral edema by detecting the level of AQP4 in cerebrospinal fluid after traumatic brain injury. The degree of edema around the hematoma after cerebral hemorrhage is independently related to the variation of the AQP4 gene. It has been studied to produce a rat water poisoning model by knocking out the AQP4 gene, and the brain tissue water content is lower than that of the water poisoning model produced by ordinary rats. And its degree of swelling around the perivascular astrocyte foot processes is also lower. It is speculated that AQP4 plays a promoting role in the occurrence and development of brain edema.
Many studies have shown that the expression of AQP4 plays a positive role in cytotoxic cerebral edema and reverses in vasogenic cerebral edema. In cytotoxic cerebral edema, the blood-brain barrier is not destroyed, and water molecules enter the brain tissue through AQP4. Therefore, when the expression of AQP4 is elevated, the more water that enters the brain tissue, the more severe the cerebral edema. In vasogenic cerebral edema, upregulation of AQP4 reduces the extent of cerebral edema. This may be because the blood-brain barrier is destroyed, and serum proteins and isotonic fluids penetrate into the intercellular space in order to adapt to changes in hydrostatic pressure, causing swelling of the intercellular space. Therefore, the formation of vasogenic cerebral edema is not involved in AQP4, but the release of water molecules during its development requires AQP4 as a mediator. Therefore, AQP4 inhibits cerebral edema in this process.
Karmacharya et al. found that the application of low-intensity ultrasound stimulation in a rat brain edema model can reduce local aggregation of AQP4. Compared with the control group, the water content of brain tissue and the expression of AQP4 were significantly reduced. Other aspects such as hypothermia treatment, decompressive craniectomy, dexamethasone and other treatments can alleviate brain edema by inhibiting the expression of AQP4, improve prognosis and improve survival rate. It is speculated that it is feasible to use AQP4 as a therapeutic target to alleviate brain edema caused by various causes.
AQP4 and Brain Tumor
glioma is the primary brain tumor with the highest incidence of the nervous system in the clinic, and it is mostly malignant invasive growth. The total surgical resection rate is low and the recurrence rate is high. It is necessary to cooperate with radiotherapy and chemotherapy and other comprehensive treatment. It is still very difficult to treat. The study found that in brain astrocytoma, high expression of AQP4 is closely related to the occurrence of peritumoral edema and the degree of malignancy of glioma. Ding et al. have shown that AQP4 is significantly increased in brain tumor cells, and glioma is more prominent. AQP4 is very likely to have a positive effect on tumor growth and promote the deterioration of the disease. AQP4 has anti-apoptotic effects in glioma cells. In addition, AQP4 can promote the migration of glioma cells, which will undoubtedly promote tumor growth and increase its invasiveness. It is speculated that artificially promoting the down-regulation of AQP4 may have an inhibitory effect on the development of glioma.
Figure 1: The new potential roles of AQP4 in glioma. (Lan, et al. 2017).
Meningioma is the intracranial tumor with a second highest incidence of glioma. Studies have shown that AQP4 is mainly expressed on the tumor cell membrane of meningioma, and its expression level is positively correlated with the severity of peritumoral edema. Therefore, it is speculated that if the AQP4 expression of tumor cells can be inhibited, peritumoral edema can be controlled. It can alleviate the symptoms of increased intracranial pressure during the operation period, reduce the risk of brain swelling during surgery and it is easier to separate tumors during surgery and reduce damage to brain tissue.
Multiple intracranial metastases are caused by tumor metastasis to the brain in other parts of the body. Men are more likely to metastasize with lung cancer, while women are more likely to metastasize to breast cancer and can be transferred to any part of the brain. Zhao et al. found that there is a large amount of AQP4 expression in the peritumoral brain tissue of multiple intracranial metastases, but there is a little AQP4 expression in tumor tissue. AQP4 was slightly stained in the brain tissue farther away from the tumor, and as the tumor approached, the AQP4 staining in the surrounding brain tissue continued to deepen. It is speculated that the expression of AQP4 is closely related to the edema of the brain tissue surrounding the multiple metastases and is a positive relation.