This study examined aquaporin 4 (AQP4) and Kir4.1 (a potassium channel subunit) in normal and diabetic adult Sprague– Dawley rats, and determined the effect of minocycline treatment. Retinal expression of the AQP4 and Kir4.1 genes was examined using double immuno fluorescence, Western blot analysis, and real-time reverse transcription—polymerase chain reaction. Retinal levels of vascular endothelial growth factor (VEGF), ionized calcium-binding adaptor molecule (Iba)-1 and interleukin (IL)-1β were also ascertained. The blood—retinal barrier (BRB) and retinal oedema were assessed using rhodamine isothiocyanate. AQP4, VEGF, Iba-1, and IL-1β mRNA and protein levels increased, and Kir4.1 mRNA and protein levels decreased, in diabetic rat retinas. Both BRB disruption and retinal oedema were also observed in these retinas. In diabetic rats, minocycline treatment decreased AQP4, VEGF, Iba-1 and IL-1β levels and retinal oedema, and increased Kir4.1 levels. These findings suggest that minocycline might be beneficial for retinal fluid clearance and reduction of retinal oedema in diabetic retinopathy.
SinghAStewartJM: Pathophysiology of diabetic macular edema. Int Ophthalmol Clin2009; 49: 1–11.
2.
ReichenbachAWurmAPannickeT: Müller cells as players in retinal degeneration and edema. Graefes Arch Clin Exp Ophthalmol2007; 245: 627–636.
3.
BringmannAReichenbachAWiedemannP: Pathomechanisms of cystoid macular edema. Ophthalmic Res2004; 36: 241–249.
4.
MoriFHikichiTTakahashiJ: Dysfunction of active transport of blood—retinal barrier in patients with clinically significant macular edema in type 2 diabetes. Diabetes Care2002; 25: 1248–1249.
5.
BellhornRW: Analysis of animal models of macular edema. Surv Ophthalmol1984; 28: 520–524.
6.
TretiachMMadiganMCWenL: Effect of Müller cell co-culture on in vitro permeability of bovine retinal vascular endothelium in normoxic and hypoxic conditions. Neurosci Lett2005; 378: 160–165.
7.
DistlerCDreherZ: Glia cells of the monkey retina—II. Müller cells. Vision Res1996; 36: 2381–2394.
8.
AshtonN: Bowman lecture. The blood—retinal barrier and vaso—glial relationships in retinal disease. Trans Ophthalmol Soc UK1965; 85: 199–230.
9.
NagelhusEAHorioYInanobeA: Immunogold evidence suggests that coupling of K+ siphoning and water transport in rat retinal Müller cells is mediated by a coenrichment of Kir4.1 and AQP4 in specific membrane domains. Glia1999; 26: 47–54.
10.
Amiry-MoghaddamMOttersenOP: The molecular basis of water transport in the brain. Nat Rev Neurosci2003; 4: 991–1001.
11.
SaadounSPapadopoulosMBellB: The aquaporin-4 water channel and brain tumour oedema. J Anat2002; 200: 528.
12.
Aoki-YoshinoKUchiharaTDuyckaertsC: Enhanced expression of aquaporin 4 in human brain with inflammatory diseases. Acta Neuropathol2005; 110: 281–288.
13.
KaurCSivakumarVYongZ: Blood– retinal barrier disruption and ultrastructural changes in the hypoxic retina in adult rats: the beneficial effect of melatonin administration. J Pathol2007; 212: 429–439.
14.
KofujiPBiedermannBSiddharthanV: Kir potassium channel subunit expression in retinal glial cells: implications for spatial potassium buffering. Glia2002; 39: 292–303.
15.
IandievITenckhoffSPannickeT: Differential regulation of Kir4.1 and Kir2.1 expression in the ischemic rat retina. Neurosci Lett2006; 396: 97–101.
16.
BialekSMillerSS: K+ and Cl− transport mechanisms in bovine pigment epithelium that could modulate subretinal space volume and composition. J Physiol1994; 475: 401–417.
17.
KradyJKBasuAAllenCM: Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy. Diabetes2005; 54: 1559–1565.
18.
RiteIMachadoACanoJ: Intracerebral VEGF injection highly upregulates AQP4 mRNA and protein in the perivascular space and glia limitans externa. Neurochem Int2008; 52: 897–903.
19.
KöllerHAllertNOelD: TNF α induces a protein kinase C-dependent reduction in astroglial K+ conductance. Neuroreport1998; 9: 1375–1378.
20.
BoscoAInmanDMSteeleMR: Reduced retina microglial activation and improved optic nerve integrity with minocycline treatment in the DBA/2J mouse model of glaucoma. Invest Ophthalmol Vis Sci2008; 49: 1437–1446.
21.
JiangWDesjardinsPButterworthRF: Cerebral inflammation contributes to encephalopathy and brain edema in acute liver failure: protective effect of minocycline. J Neurochem2009; 109: 485–493.
MurataTNakagawaKKhalilA: The relation between expression of vascular endothelial growth factor and breakdown of the blood—retinal barrier in diabetic rat retinas. Lab Invest1996; 74: 819–825.
24.
SongEYuDBoS: Evaluation of experimental animal model of diabetic retinopathy induced by STZ in the rat. Chin Ophthal Res2004; 22: 124–127 [in Chinese].
25.
Howard-JonesN: A CIOMS ethical code for animal experimentation. WHO Chron1985; 39: 51–56.
26.
LivakKJSchmittgenTD: Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCt method. Methods2001; 25: 402–408.
27.
LuJKaurCLingEA: Intraventricular macrophages in the lateral ventricles with special reference to epiplexus cells: A quantitative analysis and their uptake of fluorescent tracer injected intraperitoneally in rats of different ages. J Anat1993; 183: 405–414.
28.
AgrePKingLSYasuiM: Aquaporin water channels—from atomic structure to clinical medicine. J Physiol2002; 542: 3–16.
29.
HazamaAKozonoDGugginoWB: Ion permeation of AQP6 water channel protein. Single channel recordings after Hg2+ activation. J Biol Chem2002; 277: 29224–29230.
30.
NielsenSNagelhusEAAmiry-MoghaddamM: Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci1997; 17: 171–180.
31.
NagelhusEAMathiisenTMOttersenOP: Aquaporin-4 in the central nervous system: cellular and subcellular distribution and coexpression with KIR4.1. Neuroscience2004; 129: 905–913.
32.
KaurCSivakumarVZhangY: Hypoxia-induced astrocytic reaction and increased vascular permeability in the rat cerebellum. Glia2006; 54: 826–839.
33.
ZouYYLuJPoonDJ: Combustion smoke exposure induces up-regulated expression of vascular endothelial growth factor, aquaporin 4, nitric oxide synthases and vascular permeability in the retina of adult rats. Neuroscience2009; 160: 698–709.
34.
KleffnerIBungerothMSchiffbauerH: The role of aquaporin-4 polymorphisms in the development of brain edema after middle cerebral artery occlusion. Stroke2008; 39: 1333–1335.
35.
PannickeTIandievIUckermannO: A potassium channel-linked mechanism of glial cell swelling in the postischemic retina. Mol Cell Neurosci2004; 26: 493–502.
36.
PannickeTUckermannOIandievI: Ocular inflammation alters swelling and membrane characteristics of rat Müller glial cells. J Neuroimmunol2005; 161: 145–154.
37.
KofujiPCeelenPZahsKR: Genetic inactivation of an inwardly rectifying potassium channel (Kir4.1 subunit) in mice: phenotypic impact in retina. J Neurosci2000; 20: 5733–5740.
38.
SteinbergRHOakleyBNiemeyerG: Light-evoked changes in [K+]0 in retina of intact cat eye. J Neurophysiol1980; 44: 897–921.
39.
NewmanEAFrambachDAOdetteLL: Control of extracellular potassium levels by retinal glial cell K+ siphoning. Science1984; 225: 1174–1175.
40.
KarwoskiCJLuHKNewmanEA: Spatial buffering of light-evoked potassium increases by retinal Müller (glial) cells. Science1989; 244: 578–580.
41.
ReichenbachAHenkeAEberhardtW: K+ ion regulation in retina. Can J Physiol Pharmacol1992; 70 (suppl): S239–S247.
42.
TikkaTFiebichBLGoldsteinsG: Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci2001; 21: 2580–2588.
43.
ByeNHabgoodMDCallawayJK: Transient neuroprotection by minocycline following traumatic brain injury is associated with attenuated microglial activation but no changes in cell apoptosis or neutrophil infiltration. Exp Neurol2007; 204: 220–233.
44.
MishraMKDuttaKSahebSK: Understanding the molecular mechanism of blood—brain barrier damage in an experimental model of Japanese encephalitis: correlation with minocycline administration as a therapeutic agent. Neurochem Int2009; 55: 717–723.
45.
YaoJSShenFYoungWL: Comparison of doxycycline and minocycline in the inhibition of VEGF-induced smooth muscle cell migration. Neurochem Int2007; 50: 524–530.
KondohTUneyamaHNishinoH: Melatonin reduces cerebral edema formation caused by transient forebrain ischemia in rats. Life Sci2002; 72: 583–590.
48.
LissoniPRovelliFMaluganiF: Anti-angiogenic activity of melatonin in advanced cancer patients. Neuro Endocrinol Lett2001; 22: 45–47.
49.
ItoHYamamotoNArimaH: Interleukin-1β induces the expression of aquaporin-4 through a nuclear factor-κB pathway in rat astrocytes. J Neurochem2006; 99: 107–118.
50.
LiuXQKobayashiHJinZB: Differential expression of Kir4.1 and aquaporin 4 in the retina from endotoxin-induced uveitis rat. Mol Vis2007; 13: 309–317.
51.
PannickeTIandievIWurmA: Diabetes alters osmotic swelling characteristics and membrane conductance of glial cells in rat retina. Diabetes2006; 55: 633–639.
