Altered Expression of Aquaporin 1 and 5 in the Choroid Plexus following Preterm Intraventricular Hemorrhage

Abstract

Intraventricular hemorrhage (IVH) with posthemorrhagic ventricular dilatation (PHVD) is a common cause of hydrocephalus in infants. Dysregulation of cerebrospinal fluid (CSF) production by the choroid plexus may contribute to the development of PHVD. The aquaporins (AQPs), transmural water transporting proteins, are believed to contribute to CSF production. The aim of the study was to characterize the expression and localization of AQP1, 4 and 5 in the choroid plexus following preterm IVH. Using a preterm rabbit pup model, the mRNA expression, protein level and localization of AQP1, 4 and 5 were investigated in the choroid plexus at 24 and 72 h following IVH with PHVD. Further, AQP1, 4 and 5 expression were characterized in primary human plexus epithelial cells exposed to CSF from preterm human infants with IVH and to hemoglobin metabolites. IVH with PHVD in the immature brain caused a downregulation of AQP1 mRNA, the key AQP in CSF production, but an upregulation of AQP1 protein level with apical epithelial cell localization. Notably, AQP5 was expressed in the choroid plexus with upregulated mRNA expression and protein levels during PHVD with apical epithelial cell localization. Analysis of human choroid plexus epithelial cells in vitro, following exposure to posthemorrhagic CSF and to hemin, displayed results concordant with those observed in vivo, i.e. downregulation of AQP1 mRNA and upregulation of AQP5 mRNA expression. AQP4 was neither detectable in vivo nor in vitro. The changes observed in AQP1 and AQP5 expression in the choroid plexus suggest an adaptive response following IVH with possible functional implications for the development of PHVD.

The choroid plexus as a site of damage in hemorrhagic and ischemic stroke and its role in responding to injury

“…In the 4VO model of transient global cerebral ischemia, Akdemir et al [65] reported an increase AQP1 protein expression in the CP epithelium between 24 and 48 h of reperfusion. Similarly, Sveinsdottir et al [145] found an increase in CP Aqp1 protein expression in a preterm rabbit IVH model. However, at the mRNA level, there was a decrease in expression, an effect replicated in vitro by exposing cultured CP epithelial cells to the CSF of preterm infants with IVH or hemin.…”

“…The reason for the different protein and mRNA responses are uncertain. Interestingly, Sveinsdottir et al [145] also examined the expression of another aquaporin, Aqp5. They found a marked increase in both protein and mRNA expression in the preterm rabbit IVH model for that aquaporin and they also found increased Aqp5 mRNA after exposure of CP epithelial cells to hemin in vitro.…”

Challenges for intraventricular hemorrhage research and emerging therapeutic targets

“…Such changes may impact fluid secretion (e.g. aquaporin expression 67 ) and alter therapeutic targets.…”

“…In addition, ICV injection of hemoglobin can induce significant structural damage to the choroid plexus, paired with increased levels of cellular activation, oxidative stress, and inflammatory responses 73 . Moreover, ventricular hemoglobin can alter aquaporin expression in the choroid plexus 67 . Aquaporins are proteins that facilitate the passage of water through cell membranes and they are important in CSF production and circulation 64 .…”

Brain iron overload following intracranial haemorrhage

“…Choroid plexus cells express AQP1, which is involved in CSF production 139. However, following intraventricular injection of Hb to simulate IVH, AQP1 protein levels increased significantly and there was also an upregulation of AQP5, conveying a high degree of water permeability 140. In addition, Hb intraventricular injection resulted in ultrastructural damage to the choroid plexus that was accompanied by oxidative stress, cellular activation and an inflammatory response 141.…”