Aquaporin 4 and its Relationship with Brain Astrocytomas – Literature Review

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.

Resumo

Introdução As aquaporinas (AQPs) são uma família de proteínas de membrana que regulam a permeabilidade osmótica da membrana plasmática. Existem descritos na literatura um total de 13 tipos de aquaporinas em mamíferos, cada um com diferentes locais de expressão. Além da água, alguns AQPs permitem a passagem de glicerol e amônia, sendo chamados de aquagliceroproteínas. No sistema nervoso central, as AQPs 1 e 4 são expressas, sendo responsáveis pela regulação da água na barreira hematoencefálica. Acredita-se que esses dois AQPs participem do processo fisiopatológico que regula o comportamento de várias doenças do SNC, como trauma e tumores primários. Mais particularmente, há dados bastante controversos na literatura sobre a expressão de AQP4 em tumores e sua relação com a progressão da doença e possibilidade de tratamento.

Objetivo Este artigo tem como objetivo realizar uma revisão da literatura sobre a função e expressão da AQP4 no SNC e tumores primários deste sistema, a fim de compilar o que está na literatura sobre o assunto e levantar novas hipóteses de pesquisa possíveis.

Método A plataforma PUBMED foi utilizada para levantamento bibliográfico utilizando “Aquaporin 4,” “expression” e “astrocitomas” como palavras-chave. Artigos com idade superior a 2008 e artigos que não abordaram a expressão de AQP4 em astrocitomas foram excluídos. Nos artigos selecionados, foram investigados os seguintes tópicos: estrutura da AQP4, localização do cérebro e do tumor e relação com o edema peritumoral.

Resultados Em relação à estrutura e localização da AQP4, a literatura apresenta duas isoformas da AQP4: M1 e M23. Ambos formam aglomerados de AQP4 chamados “arranjos ortogonais de proteínas - OAPs.” No tecido tumoral, a literatura mostra uma diminuição na formação de OAPs e um aumento na expressão de ambas as isoformas AQP4, além de perder sua polaridade, difundindo através da membrana citoplasmática. Quanto à função da AQP4 nos tumores, a AQP4 auxilia na migração e invasão celular, além de participar da proliferação celular e apoptose. Em relação à relação com o edema cerebral, existem controvérsias. Estudos demonstram que o aumento da AQP4 agrava o edema citotóxico das células tumorais e, auxiliando na migração celular e na angiogênese, auxilia indiretamente na formação de edema vasogênico por quebra da barreira hematoencefálica. Outros estudos, no entanto, apontam para o aumento da AQP4 como mecanismo protetor para combater o edema vasogênico que ocorre na formação de tumores. Além disso, a literatura apresenta uma proposta terapêutica em que, ao inibir a expressão da AQP4, a migração tumoral e o edema cerebral diminuem em ratos com glioblastoma.

Discussão Como mostrado na literatura, há uma diferença na estrutura histopatológica entre os gliomas de alto e baixo grau. No entanto, existem mudanças comuns entre eles. Estas alterações comuns poderiam então ser usadas como um fator de gravidade ou evolução de tumores de baixo grau a alto grau. Além disso, ainda não é possível perceber a verdadeira relação entre a expressão da AQP4 e o aumento da evolução do VEGF no edema peritumoral. Finalmente, pode-se supor que, como a razão de expressão entre as isoformas de AQP4 no tecido normal é maior do que em alguns tumores, a diminuição dessa razão é devida à diminuição da expressão de M23 ou ao aumento da isoforma M1.

Conclusão: Novos estudos são necessários para compreender a fisiologia e a fisiopatologia da AQP4 em astrocitomas, a fim de criar propostas terapêuticas efetivas para combater essa doença.

Keywords

Expression - Aquaporin 4 - Gliomas - CNS

Publication History

Received: 18 April 2021

Accepted: 16 June 2021

Article published online:
28 June 2023

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