Changes in Ocular Aquaporin-4 (AQP4) Expression Following Retinal Injury

Overview

Journal Mol Vis

Specialties Cell Biology
Molecular Biology
Ophthalmology

Date 2008 Oct 7

PMID 18836575

Citations 22

Authors

Adnan Dibas

Ming-Hui Yang

Shaoqing He

Joseph Bobich

Thomas Yorio

Affiliations

Soon will be listed here.

Abstract

Purpose: Changes in the expression of water channels or aquaporins (AQP) have been reported in several diseases. However, such changes and mechanisms remain to be evaluated for retinal injury. This study was designed to analyze changes in the expression of AQP4 following elevation of intraocular pressure (IOP) and after intravitreal endothelin-1 injection and the potential involvement of the ubiquitin-dependent proteasome.

Methods: Retinal injuries were induced by the elevation of intraocular pressure in rat eyes using the Morrison model or following endothelin-1 intravitreal injection. Immunohistochemistry using a combination of glial fibrillary acidic protein (GFAP) and aquaporin-4 antibodies were employed to follow changes in the optic nerve head astrocytes. Real-time quantitative PCR (Q-PCR) was used for measuring changes in AQP4, ubiquitin hydrolase L1 (UCH-L1), and beta-actin messages. Changes in AQP4, caspase-3, thy-1, ubiquitination, and GFAP expression were also followed in total retinal extracts using western blotting. An S5a column was used to purify ubiquitinated proteins.

Results: In retinas of both injury models, there was an upregulation of GFAP (a marker of astrogliosis), caspase-3, and downregulation of thy-1, a marker for retinal ganglion cell stress, and decreased retinal AQP4 mRNA and protein levels as determined by Q-PCR, and western blotting, respectively. By contrast, IOP enhanced expression and co-localization of GFAP and AQP4 in optic nerve astrocytes. AQP4 was detected in affinity-purified ubiquitinated proteins using S5a column, suggesting that AQP4 is a target for degradation by the ubiquitin-dependent proteasome. While elevation of IOP induced an increase in ubiquitination in retinal extracts, it decreased ubiquitination in optic nerve extracts as detected by western blotting. Enhanced ubiquitination and decreased ubiquitination appear to correlate with AQP4 expression. IOP decreased UCH-L1 (or protein gene protein [PGP9.5]) in retinal extracts as judged by Q-PCR.

Conclusions: The enhanced expression of AQP4 in optic nerve astrocytes following elevation of IOP may explain the astrocytic hypertrophy normally seen in glaucoma patients and may involve alteration in the activity of ubiquitin-dependent proteasomal degradation system. The decreased ubiquitination in the optic nerve may lead to increased levels of proapoptotic proteins known to be degraded by the proteasome, and thus to axonal degeneration in glaucoma.

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References

Johnson E, Deppmeier L, Wentzien S, Hsu I, Morrison J . Chronology of optic nerve head and retinal responses to elevated intraocular pressure. Invest Ophthalmol Vis Sci. 2000; 41(2):431-42. View

Walz W . Role of astrocytes in the clearance of excess extracellular potassium. Neurochem Int. 2000; 36(4-5):291-300. DOI: 10.1016/s0197-0186(99)00137-0. View

Hernandez M . The optic nerve head in glaucoma: role of astrocytes in tissue remodeling. Prog Retin Eye Res. 2000; 19(3):297-321. DOI: 10.1016/s1350-9462(99)00017-8. View

Preisser L, Teillet L, Aliotti S, Gobin R, Berthonaud V, Chevalier J . Downregulation of aquaporin-2 and -3 in aging kidney is independent of V(2) vasopressin receptor. Am J Physiol Renal Physiol. 2000; 279(1):F144-52. DOI: 10.1152/ajprenal.2000.279.1.F144. View

Kermer P, Ankerhold R, Klocker N, Krajewski S, Reed J, Bahr M . Caspase-9: involvement in secondary death of axotomized rat retinal ganglion cells in vivo. Brain Res Mol Brain Res. 2001; 85(1-2):144-50. DOI: 10.1016/s0169-328x(00)00256-4. View

Flammer J, Pache M, Resink T . Vasospasm, its role in the pathogenesis of diseases with particular reference to the eye. Prog Retin Eye Res. 2001; 20(3):319-49. DOI: 10.1016/s1350-9462(00)00028-8. View

Suzuki Y, Nakabayashi Y, Takahashi R . Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death. Proc Natl Acad Sci U S A. 2001; 98(15):8662-7. PMC: 37492. DOI: 10.1073/pnas.161506698. View

NEWMAN E, Frambach D, Odette L . Control of extracellular potassium levels by retinal glial cell K+ siphoning. Science. 1984; 225(4667):1174-5. PMC: 2693189. DOI: 10.1126/science.6474173. View

NEWMAN E . Distribution of potassium conductance in mammalian Müller (glial) cells: a comparative study. J Neurosci. 1987; 7(8):2423-32. PMC: 6568979. View

10.

Morrison J, Dunkelberger G, Quigley H . Optic nerve head extracellular matrix in primary optic atrophy and experimental glaucoma. Arch Ophthalmol. 1990; 108(7):1020-4. DOI: 10.1001/archopht.1990.01070090122053. View

11.

Coleman A, Quigley H, Vitale S, Dunkelberger G . Displacement of the optic nerve head by acute changes in intraocular pressure in monkey eyes. Ophthalmology. 1991; 98(1):35-40. DOI: 10.1016/s0161-6420(91)32345-5. View

12.

Bizzi A, Schaetzle B, Patton A, Gambetti P . Axonal transport of two major components of the ubiquitin system: free ubiquitin and ubiquitin carboxyl-terminal hydrolase PGP 9.5. Brain Res. 1991; 548(1-2):292-9. DOI: 10.1016/0006-8993(91)91135-n. View

13.

Schlamp C, Johnson E, Li Y, Morrison J, Nickells R . Changes in Thy1 gene expression associated with damaged retinal ganglion cells. Mol Vis. 2001; 7:192-201. View

14.

Yamamoto N, Sobue K, Miyachi T, Inagaki M, Miura Y, Katsuya H . Differential regulation of aquaporin expression in astrocytes by protein kinase C. Brain Res Mol Brain Res. 2001; 95(1-2):110-6. DOI: 10.1016/s0169-328x(01)00254-6. View

15.

Kallberg M, Brooks D, Garcia-Sanchez G, Komaromy A, Szabo N, Tian L . Endothelin 1 levels in the aqueous humor of dogs with glaucoma. J Glaucoma. 2002; 11(2):105-9. DOI: 10.1097/00061198-200204000-00005. View

16.

McKinnon S, Lehman D, Merges C, Pease M, Kerrigan D, Ransom N . Caspase activation and amyloid precursor protein cleavage in rat ocular hypertension. Invest Ophthalmol Vis Sci. 2002; 43(4):1077-87. View

17.

Agre P, King L, Yasui M, Guggino W, Ottersen O, Fujiyoshi Y . Aquaporin water channels--from atomic structure to clinical medicine. J Physiol. 2002; 542(Pt 1):3-16. PMC: 2290382. DOI: 10.1113/jphysiol.2002.020818. View

18.

Stokely M, Brady S, Yorio T . Effects of endothelin-1 on components of anterograde axonal transport in optic nerve. Invest Ophthalmol Vis Sci. 2002; 43(10):3223-30. View

19.

Holthoff K, Witte O . Intrinsic optical signals in rat neocortical slices measured with near-infrared dark-field microscopy reveal changes in extracellular space. J Neurosci. 1996; 16(8):2740-9. PMC: 6578770. View

20.

Cioffi G, Orgul S, Onda E, Bacon D, Van Buskirk E . An in vivo model of chronic optic nerve ischemia: the dose-dependent effects of endothelin-1 on the optic nerve microvasculature. Curr Eye Res. 1995; 14(12):1147-53. DOI: 10.3109/02713689508995821. View