Aquaporin 4 and its Relationship with Brain Astrocytomas – Literature Review
Authors: Vieira Raphael Vinícius Gonzaga , Farias Rafaela , Peres Manuela Correa de Toledo , Seba Maria Clara , Aguiar Paulo Henrique Pires de 
Published: June 2023

Abstract
Background Aquaporins (AQPs) are a family of membrane proteins that regulate the osmotic permeability of the plasma membrane. There are described in the literature a total of 13 types of Aquaporins in mammals, each with different places of expression. In addition to water, some AQPs allow the passage of glycerol and ammonia, being called Aquaglyceroproteins. In the central nervous system, AQPs 1 and 4 are expressed, being responsible for the water regulation in the blood-brain barrier. These two AQPs are believed to participate in the pathophysiological process that governs the behavior of various CNS diseases, such as trauma and primary tumors. More particularly, there are quite controversial data in the literature on the expression of AQP4 in tumors and its relationship with disease progression and treatment possibility.
Objective This paper aims to perform a literature review on the function and expression of AQP4 in the CNS and primary tumors of this system, to compile what is in the literature on the subject and raise new possible research hypotheses.
Methods The PUBMED platform was used for bibliographic survey using “Aquaporin 4,” “expression” and “astrocytomas” as keywords. Articles older than 2008 and articles that did not address AQP4 expression in astrocytomas were excluded. In the selected articles, the following topics were investigated: AQP4 structure, brain and tumor localization, and relationship with peritumoral edema.
Results Regarding the structure and location of AQP4, the literature presents two isoforms of AQP4: M1 and M23. Both form clusters of AQP4 called “orthogonal arrays of proteins - OAPs.” In the tumor tissue, the literature shows a decrease in the formation of OAPs and an increase in the expression of both AQP4 isoforms, besides losing their polarity, diffusing through the cytoplasmic membrane. As for the function of AQP4 in tumors, AQP4 assists in cell migration and invasion, in addition to participating in cell proliferation and apoptosis. Regarding the relationship with cerebral edema, there are controversial knowledge. Studies have shown that increased AQP4 aggravates cytotoxic edema of tumor cells and, by assisting in cell migration and angiogenesis, indirectly assist in the formation of vasogenic edema by breaking the blood-brain barrier. Other studies, however, point to the increase in AQP4 as a protective mechanism to combat vasogenic edema that occurs in tumor formation. Furthermore, the literature presents a therapeutic proposal in which, by inhibiting AQP4 expression, tumor migration and cerebral edema decrease in rats with glioblastoma.
Discussion As shown in the literature, there is a difference in histopathological structure between high and low grade gliomas. However, there are common changes between them. These common changes could then be used as a factor of severity or evolution of low-grade to high-grade tumors. Moreover, it is not yet possible to perceive the true relationship of AQP4 expression and increased VEGF evolution of peritumoral edema. Finally, it can be hypothesized that since the expression ratio between AQP4 isoforms in normal tissue is greater than in some tumors, the decrease in this ratio is due either to decreased M23 expression or increased of the isoform M1.
Conclusion Further studies are needed to understand the physiology and pathophysiology involving AQP4 in astrocytomas to create effective therapeutic proposals to combat this disease.