Abstract
It is recognized that expression of AQP4 protein is much greater in gliomas than in normal tissue. The relationship between AQP4 and glioma-associated brain edema is affected by osmotic pressure and hypoxia. In this study, we detected changes of AQP4 expression in tumor and peritumoral edematous tissues to analyze the relationship between AQP4 protein and the edema index (EI). We also detected expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) to investigate their relationship with AQP4 protein, and thus to uncover the molecular biological mechanisms of AQP4 expression in glioma-associated brain edema. Sixty-five patients with brain glioma were divided into tumor and peritumor groups. Fresh tumor specimens, including six cases of grade I glioma, 18 of grade II, 11 of grade III and 30 of grade IV, and peritumoral edematous tissue specimens (1 cm distant from the tumor) were resected from these patients, and AQP4 protein expression levels were detected by western blot. Different AQP4 expression in the tumor and peritumor groups were compared. The relationship between AQP4 expression levels and the degree of peritumoral edema, and expression differences in different grades, were analyzed. Immunofluorescence cytochemistry was used to detect positive expression of AQP4 protein, VEGF protein, and HIF-1α protein in tumor tissue, and differences between expression were analyzed. Western blot showed that AQP4 expression in the peritumor (0.7697 ± 0.0941) and tumor (0.6934 ± 0.0625) groups was higher than in the control group (0.6215 ± 0.0884), and was highest in the peritumor group (both P < 0.01). AQP4 expression level in the peritumor group was positively correlated with EI (r = 0.677, P < 0.001) whereas AQP4 expression level in the tumor group was not correlated with EI (r = 0.096, P > 0.05). AQP4 expression increased with higher tumor grades in the peritumor group, but differences were not significant in the tumor group. Immunofluorescence cytochemical staining revealed that AQP4 protein in normal brain tissue was mainly expressed in the cell membrane surface, and that cytoplasm and nuclear staining was shallow. In glioma cells, AQP4 was widely distributed in the cytoplasm, particularly in the edematous area around the tumor. AQP4 protein expression in the tumor was significantly positively correlated with both VEGF protein (r = 0.877, P < 0.001) and HIF-1α protein (r = 0.876, P < 0.001). AQP4 expression was higher in brain tumor, especially peritumor. The degree of peritumoral edema correlates with AQP4 protein expression only in peritumor, whereas AQP4 expression is in accordance with expression of VEGF and HIF-1α. In glioma-associated brain edema, AQP4 is coregulated by osmotic pressure and hypoxia, with predominance of osmotic regulation, and is redistributed in glioma cells, mainly in the cytoplasm, and its expression level increased with higher glioma grades.
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References
Betz AL, Iannotti F, Hoff JT (1989) Brain edema: a classification based on blood–brain barrier integrity. Cerebrovasc Brain Metab Rev 1(2):133–154
McCoy Eric, Sontheimer Harald (2007) Expression and function of water channels (aquaporins) in migrating malignant astrocytes. Glia 55(10):1034–1043
Gunnarson E, Zelenina M, Aperia A (2004) Regulation of brain aquaporins. Neuroscience 129:947–955
Yamamoto N, Yoneda K, Asai K et al (2001) Alterations in the expression of the AQP family in cultured rat astrocytes during hypoxia and reoxygenation. Molec Brain Res. 90(1):26–38
Fu XM, Yao YJ, Yang Z et al (2005) Alteration and its significance to expression of aquaporin-4 in cultured neonatal rat astrocytes in the model of hypoxic damage. J Sichuan Univ (Med Sci Ed) 36(5):641–644
Tomas-Camardiel M, Venero JL, Herrera AJ et al (2005) Blood–brain barrier disruption highly induces aquaporin-4 mRNA and protein in perivascular and parenchymal astrocytes: protective effect by estradiol treatment in ovariectomized animals. J Neurosci Res 80(2):235–246
Warth A, Simon P, Capper D (2007) Expression pattern of the water channel aquaporin-4 in human gliomas is associated with blood–brain barrier disturbance but not with patient survival. J Neurosci Res 85:1336–1346
Kazuhiro Y, Yamamoto N, Asai K et al (2001) Regulation of aquaporin-4 expression in astrocytes. Molec Brain Res 89(2):94–102
Hurst RD, Fritz IB (1996) Properties of an immortalised vascular endothelial/glioma cell co-culture model of the blood–brain barrier. J Cell Phys 167(1):81–88
Stewart PA, Hayakawa K, Hayakawa E et al (1985) A quantitative study of blood–brain barrier permeability ultrastructure in a new rat glioma model. Acta Neuropathol 67(1–2):96–102
Warth A, Mittelbronn M, Wolburg H (2005) Redistribution of the water channel protein aquaporin-4 and the K + channel protein Kir 4 differs in low- and high-grade human brain tumors. Acta Neuropathol (Ber1) 109(4):418–426
Yang B, Zador Z, Verkman AS (2008) Glial cell aquaporin-4 overexpression in transgenic mice accelerates cytotoxic brain swelling. J Bio Chem 283(22):15280–15286
Amiry-Moghaddam M, Frydenlund DS, Ottersen OP (2004) Anchoring of aquaporin-4 in brain: molecular mechanisms and implications for the physiology and pathophysiology of water transport. Neuroscience 129(4):999–1010
Warth A, Kröger S, Wolburg H (2004) Redistribution of aquaporin-4 in human glioblastoma correlates with loss of agrin immunoreactivity from brain capillary basal laminae. Acta Neuropathol 107:311–318
Zeynalov E, Chen CH, Froehner SC et al (2008) The perivascular pool of aquaporin-4 mediates the effect of osmotherapy in postischemic cerebral edema. Criti Care Med 36(9):2634–2640
Chanson M, Kotsias BA, Peracchia C et al (2007) Interactions of connexins with other membrane channels and transporters. Prog Biophys Mol Biol 94:233–244
Binder DK, Yao X, Sick TJ (2006) Increased seizure duration and slowed potassium kinetics in mice lacking aquaporin-4 water channels. Glia 53:631–636
Meng S, Qiao M, Lin L et al (2004) Correspondence of AQP4 expression and hypoxic-ischaemic brain oedema monitored by magnetic resonance imaging in the immature and juvenile rat. Eur J Neurosci 19(8):2261–2269
Manley GT, Binder DK, Papadopoulos MC et al (2004) New insights into water transport and edema in the central nervous system from phenotype analysis of aquaporin-4 null mice. Neuroscience 129(4):983–991
Papadopoulos MC, Manley GT, Krishna S et al (2004) Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema. FASEB J 18(11):1291–1293
Hu H, Yao HT, Zhang WP et al (2005) Increased expression of aquaporin-4 in human traumatic brain injury and brain tumors. J Zhejiang Univ (China) Sci B 6(1):33–37
Saadoun S, Papadopoulos MC, Watanabe H (2005) Involvement of aquaporin-4 in astroglial cell migration and glial scar formation. J Cell Sci 118(Pt 24):5691–5698
Rite I, Machado A, Cano J et al (2008) Intracerebral VEGF injection highly upregulates AQP4 mRNA and protein in the perivascular space and glia limitans externa. Neurochem Intern 52(4–5):897–903
Bingmei MF, Shen S (2003) Structural mechanisms of acute VEGF effect on microvessel permeability. Am J Physiol Heart Circ Physiol 284:H2124–H2135
Huang C-T, Chang D-K (2008) Anti-angiogenic therapeutic drugs for treatment of human cancer. J Cancer Mol 4(2):37–45
Thickett DR, Armstrong L, Millar AB (1999) Vascular endothelial growth factor (VEGF) in inflammatory and malignant pleural effusions. Thorax 54:707–710
Tarbell JM (2000) Effect of VEGF on retinal microvascular endothelial hydraulic conductivity: the role of NO. Invest Ophthalmol Vis Sci 41:4256–4261
Liu LX, Lu H, Luo Y et al (2002) Stabilization of vascular endothelial growth factor mRNA by hypoxia-inducible factor 1. Biochem Biophys Res Commun 291(4):908–914
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Mou, K., Chen, M., Mao, Q. et al. AQP-4 in peritumoral edematous tissue is correlated with the degree of glioma and with expression of VEGF and HIF-alpha. J Neurooncol 100, 375–383 (2010). https://doi.org/10.1007/s11060-010-0205-x
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DOI: https://doi.org/10.1007/s11060-010-0205-x