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AQP9 (aquaporin 9) was first discovered in adipose tissue, and the AQP9 gene was successfully cloned. There are also AQP9 in tissues such as testis, spleen, white blood cells, liver, and brain. AQP9 belongs to the sub-group of hydroglycerin channels and is transparent to many small molecules such as water, urea, guanidine and pyrimidine. AQP9 is abundant in brain tissue and is distributed in the central nervous system on the cell membranes of astrocytes, vascular endothelial cells, and special types of catecholamine-like neurons. Compared with other AQPs, AQP9 is unique in structure, distribution, and function.
Figure 1. Signaling pathways reported thus far to be involved in regulating the hepatic expression of AQP9. (Lebeck. 2014).
The human AQP9 gene is located on the chromosome 15q21.3 and contains 6 exons. The AQP9 protein is a glycoprotein polypeptide chain with a relative molecular mass of 300 kDa and the same basic structure as other AQPs. Each of the aqueous pores of AQP9 has independent water permeabilization activity, and the basic structure constituting these water pores is an α-helix of 6 times across the cell membrane. The four monomers consisting of these α helices form homotetramers which form a high-order structure of AQP9 with a central void. The homotetramer is only distributed on the cell membrane, and this distribution characteristic is a prerequisite for maintaining the stability and normal function of AQP9.
In the distribution and localization study of AQP9, Wang et al. found that AQP9 is mainly distributed in astrocytes of the periventricular organs, choroid plexus, subgingival organs and periventricular parenchyma. Because the main physiological functions of the organs around the ventricle are involved in cerebrospinal fluid reflux and regulate the activity of neuroactive substances, suggesting that AQP9 may be involved in regulating cerebrospinal fluid circulation, maintaining central nervous system stability, and maintaining brain energy metabolism balance.
AQP9 Regulation in Brain Tissue
Regulation of AQP9 by Hormone
AQP9 is permeable to brain energetic substances such as glycerol and monocarboxylic acid and AQP9 is expressed in catecholamine-like neurons. As a result, these neurons are associated with energy metabolism balance and diabetic neuroendocrine function. In addition, it is known that intracerebral injection of insulin is also associated with energy metabolism balance. The researchers studied the effect of insulin on the expression of AQP9 in brain tissue through a rat model of in vivo diabetes and in vitro cell culture, and used immunohistochemistry to determine the expression pattern of AQP9 cells affected by insulin. It was found that in the brain tissue of diabetic rats, AQP9 expression was only increased in catecholamine-like neurons, but there was no change in AQP9 content in cerebral cortex and cerebellum.
Diabetic rat models and in vitro brain tissue sections showed that the expression level of brain AQP9 can be regulated by different concentrations of insulin. It is speculated that central nervous system AQP9 is related to brain energy metabolism. In addition, a study on the regulation mechanism of AQP9 by in vitro astrocyte culture revealed that protein kinase A (PKA) and protein kinase C (PKC) pathways are the main pathways of insulin to the regulation of AQP9. Activation of the PKC pathway downregulates AQP9 mRNA and protein. Yamamoto et al. also found that PKA catalyst (db-cAMP) and PKA inhibitor (cycloheximide) can increase and decrease AQP9 expression, respectively, indicating that PKA pathway can up-regulate AQP9 expression.
Regulation of AQP9 by Hypoxia
Potomar et al. used RT-PCR to detect changes in the expression level of AQP9 gene during hypoxia and reoxygenation. It was found that AQP9 was mainly expressed on the astrocyte membrane; AQP9 mRNA showed a decrease in the first expression of hypoxia to reoxygenation and then increased gradually. The expression level of AQP9 mRNA was the same as that of the control group at 6 h after reoxygenation, and it was more than 2 times higher than the normal level after 9 h, indicating that the expression of AQP9 gene on the plasma membrane of astrocytes can be regulated by hypoxia.
Regulation of AQP9 by Osmotic Pressure
The study found that the AQP9 promoter region contains hyperosmotic response elements. Juutiuusitalo et al. studied the expression and regulation of AQP9 mRNA and protein in rat brain tissue under hypertonic conditions by applying hypertonic mannitol to cultured mouse astrocytes and injecting mannitol into the abdominal cavity of mice. The results showed that AQP9 gene and protein on astrocyte membrane were down-regulated by the p38MAPK inhibitor, while extracellular signal-regulated kinase (ERK) inhibitor and c-Jun N-terminal kinase (JNK) inhibitor had no effect on AQP9 expression. It is speculated that p38MAPK may be the major signal transduction pathway of AQP9 under hypertonic conditions.
AQP9 and Brain Disease
The study found that AQP9 expression is also present in special types of catecholamines such as adrenergic, noradrenergic, and dopaminergic neurons. It is speculated that the expression of AQP9 in such special neurons may be related to energy metabolism. Karlsson et al. used peroxidase immunofluorescence labeling to study the distribution of AQP9 in brain tissue of rats with cerebral ischemia-reperfusion. The results showed that the AQP9 immunolabeling of astrocytes around the ventricles was significantly increased. The periventricular organs include the lower organs of the humerus and the hypothalamus. They lack the blood-brain barrier and play an important role in the reflux of cerebrospinal fluid and the regulation of physiological functions of vasoactive substances. The distribution of AQP9 at the above sites suggests that AQP9 may be involved in regulating cerebrospinal fluid circulation, maintaining brain metabolic balance, maintaining normal function of brain cells and stabilizing the internal environment.
Intracranial hemorrhage (ICH) is a common subtype of stroke with high morbidity and mortality. AQP9 plays a key role in brain edema after ischemic stroke and traumatic brain injury and participates in the regulation of angiogenesis. Ji et al. have suggested that the AQP9 in the brain may play a compensatory role in the ICH response, promoting cerebral angiogenesis, and preventing subsequent neuronal death, thus AQP9 can prevent the deterioration of the ICH neurologic results. Wei et al. have studied the ischemic brain of rats with permanent middle cerebral artery occlusion (PMCAO) to elucidate the expression pattern of AQP9 and p38 mitogen activated protein kinase (MAPK) after ischemia. The results indicate that the dynamic changes of AQP9 expression mediated by p38MAPK signal transduction pathway may contribute to the development of cerebral edema after cerebral ischemia.