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Impaired Purinergic Regulation of the Glial (Müller) Cell Volume in the Retina of Transgenic Rats Expressing Defective Polycystin-2

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Abstract

Retinal glial (Müller) cells possess an endogenous purinergic signal transduction cascade which normally prevents cellular swelling in osmotic stress. The cascade can be activated by osmotic or glutamate receptor-dependent ATP release. We determined whether activation of this cascade is altered in Müller cells of transgenic rats that suffer from a slow photoreceptor degeneration due to the expression of a truncated human cilia gene polycystin-2 (CMV-PKD21/703 HA). Age-matched Sprague–Dawley rats served as control. Retinal slices were superfused with a hypoosmotic solution (60 % osmolarity). Müller cells in retinas of PKD21/703 rats swelled immediately in hypoosmotic stress; this was not observed in control retinas. Pharmacological blockade of P2Y1 or adenosine A1 receptors induced osmotic swelling of Müller cells from control rats. The swelling induced by the P2Y1 receptor antagonist was mediated by induction of oxidative–nitrosative stress, mitochondrial dysfunction, production of inflammatory lipid mediators, and a sodium influx from the extracellular space. Exogenous VEGF or glutamate prevented the hypoosmotic swelling of Müller cells from PKD21/703 rats; this effect was mediated by activation of the purinergic signaling cascade. In neuroretinas of PKD21/703 rats, the gene expression levels of P2Y1 and A1 receptors, pannexin-1, connexin 45, NTPDases 1 and 2, and various subtypes of nucleoside transporters are elevated compared to control. The data may suggest that the osmotic swelling of Müller cells from PKD21/703 rats is caused by an abrogation of the osmotic ATP release while the glutamate-induced ATP release is functional. In the normal retina, ATP release and autocrine P2Y1 receptor activation serve to inhibit the induction of oxidative–nitrosative stress, mitochondrial dysfunction, and production of inflammatory lipid mediators, which otherwise will induce a sodium influx and cytotoxic Müller cell swelling under anisoosmotic conditions. Purinergic receptors may represent a target for the protection of retinal glial cells from mitochondrial oxidative stress.

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Abbreviations

AOPCP:

Adenosine-5′-O-(α,β-methylene)-diphosphate

ARL-67156:

6-N,N-diethyl-D-β,γ-dibromomethylene ATP

ATP:

Adenosine 5′-triphosphate

BAPTA/AM:

Bis-(o-aminophenoxy)ethane-N,N,N′,N′-tetra-acetic acid acetoxymethyl ester

CNT:

Concentrative nucleoside transporter

DPCPX:

8-Cyclopentyl-1,3-dipropylxanthine

ENT:

Equilibrative nucleoside transporters

Kir:

Inwardly rectifying potassium

L-NAME:

Nω-nitro-l-arginine methyl ester hydrochloride

LY341495:

(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid

MRS2179:

N 6-Methyl-2′-deoxyadenosine-3′,5′-bisphosphate

NBTI:

N-Nitrobenzylthioinosine

NPPB:

5-Nitro-2-(3-phenylpropylamino)benzoic acid

NTPDase:

Nucleoside triphosphate diphosphohydrolase

PKD:

Polycystic kidney disease

SU1498:

(E)-3-(3,5-diisopropyl-4-hydroxyphenyl)-2-[(3-phenyl-n-propyl)amino-carbonyl]acrylnitrile

VEGF:

Vascular endothelial growth factor

References

  1. Balboa MA, Balsinde J (2006) Oxidative stress and arachidonic acid mobilization. Biochim Biophys Acta 1761:385–391

    Article  CAS  PubMed  Google Scholar 

  2. Barot M, Gokulgandhi MR, Mitra AK (2011) Mitochondrial dysfunction in retinal diseases. Curr Eye Res 36:1069–1077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Birkle DL, Bazan NG (1989) Light exposure stimulates arachidonic acid metabolism in intact rat retina and isolated rod outer segments. Neurochem Res 14:185–190

    Article  CAS  PubMed  Google Scholar 

  4. Bresnick GH (1983) Diabetic maculopathy. A critical review highlighting diffuse macular edema. Ophthalmology 90:1301–1317

    Article  CAS  PubMed  Google Scholar 

  5. Bringmann A, Uckermann O, Pannicke T, Iandiev I, Reichenbach A, Wiedemann P (2005) Neuronal versus glial cell swelling in the ischaemic retina. Acta Ophthalmol Scand 83:528–538

    Article  PubMed  Google Scholar 

  6. Bringmann A, Pannicke T, Grosche J, Francke M, Wiedemann P, Skatchkov SN, Osborne NN, Reichenbach A (2006) Müller cells in the healthy and diseased retina. Prog Retin Eye Res 25:397–424

    Article  CAS  PubMed  Google Scholar 

  7. Chebabo SR, Hester MA, Aitken PG, Somjen GG (1995) Hypotonic exposure enhances synaptic transmission and triggers spreading depression in rat hippocampal tissue slices. Brain Res 695:203–216

    Article  CAS  PubMed  Google Scholar 

  8. Chua J, Nivison-Smith L, Fletcher EL, Trenholm S, Awatramani GB, Kalloniatis M (2013) Early remodeling of Müller cells in the rd/rd mouse model of retinal dystrophy. J Comp Neurol 521:2439–2453

    Article  CAS  PubMed  Google Scholar 

  9. Dmitriev AV, Govardovskii VI, Schwahn HN, Steinberg RH (1999) Light-induced changes of extracellular ions and volume in the isolated chick retina-pigment epithelium preparation. Vis Neurosci 16:1157–1167

    Article  CAS  PubMed  Google Scholar 

  10. Felmy F, Pannicke T, Richt JA, Reichenbach A, Guenther E (2001) Electrophysiological properties of rat retinal Müller (glial) cells in postnatally developing and in pathologically altered retinae. Glia 34:190–199

    Article  CAS  PubMed  Google Scholar 

  11. Feng Y, Wang Y, Stock O, Pfister F, Tanimoto N, Seeliger MW, Hillebrands JL, Hoffmann S, Wolburg H, Gretz N, Hammes HP (2009) Vasoregression linked to neuronal damage in the rat with defect of polycystin-2. PLoS One 4:e7328

    Article  PubMed  PubMed Central  Google Scholar 

  12. Gallagher AR, Hoffmann S, Brown N, Cedzich A, Meruvu S, Podlich D, Feng Y, Könecke V, de Vries U, Hammes HP, Gretz N, Witzgall R (2006) A truncated polycystin-2 protein causes polycystic kidney disease and retinal degeneration in transgenic rats. J Am Soc Nephrol 17:2719–2730

    Article  CAS  PubMed  Google Scholar 

  13. Garcia TB, Pannicke T, Vogler S, Berk BA, Grosche A, Wiedemann P, Seeger J, Reichenbach A, Herculano AM, Bringmann A (2014) Nerve growth factor inhibits osmotic swelling of rat retinal glial (Müller) and bipolar cells by inducing glial cytokine release. J Neurochem 131:303–313

    Article  CAS  PubMed  Google Scholar 

  14. Hirrlinger PG, Wurm A, Hirrlinger J, Bringmann A, Reichenbach A (2008) Osmotic swelling characteristics of glial cells in the murine hippocampus, cerebellum, and retina in situ. J Neurochem 105:1405–1417

    Article  CAS  PubMed  Google Scholar 

  15. Iandiev I, Biedermann B, Bringmann A, Reichel MB, Reichenbach A, Pannicke T (2006) Atypical gliosis in Müller cells of the slowly degenerating rds mutant mouse retina. Exp Eye Res 82:449–457

    Article  CAS  PubMed  Google Scholar 

  16. Iandiev I, Pannicke T, Hollborn M, Wiedemann P, Reichenbach A, Grimm C, Remé CE, Bringmann A (2008) Localization of glial aquaporin-4 and Kir4.1 in the light-injured murine retina. Neurosci Lett 434:317–321

    Article  CAS  PubMed  Google Scholar 

  17. Jayakumar AR, Rao KV, Panickar KS, Moriyama M, Reddy PV, Norenberg MD (2008) Trauma-induced cell swelling in cultured astrocytes. J Neuropathol Exp Neurol 67:417–427

    Article  CAS  PubMed  Google Scholar 

  18. Karl A, Wurm A, Pannicke T, Krügel K, Obara-Michlewska M, Wiedemann P, Reichenbach A, Albrecht J, Bringmann A (2011) Synergistic action of hypoosmolarity and glutamine in inducing acute swelling of retinal glial (Müller) cells. Glia 59:256–266

    Article  PubMed  Google Scholar 

  19. Kaur C, Sivakumar V, Yong Z, Lu J, Foulds WS, Ling EA (2007) Blood-retinal barrier disruption and ultrastructural changes in the hypoxic retina in adult rats: the beneficial effect of melatonin administration. J Pathol 212:429–439

    Article  CAS  PubMed  Google Scholar 

  20. Krishnan G, Chatterjee N (2013) Detergent resistant membrane fractions are involved in calcium signaling in Müller glial cells of retina. Int J Biochem Cell Biol 45:1758–1766

    Article  CAS  PubMed  Google Scholar 

  21. Krügel K, Wurm A, Linnertz R, Pannicke T, Wiedemann P, Reichenbach A, Bringmann A (2010) Erythropoietin inhibits osmotic swelling of retinal glial cells by Janus kinase and extracellular signal-regulated kinases1/2-mediated release of vascular endothelial growth factor. Neuroscience 165:1147–1158

    Article  PubMed  Google Scholar 

  22. Krügel K, Wurm A, Pannicke P, Hollborn M, Karl A, Wiedemann P, Reichenbach A, Kohen L, Bringmann A (2011) Involvement of oxidative stress and mitochondrial dysfunction in the osmotic swelling of retinal glial cells from diabetic rats. Exp Eye Res 92:87–93

    Article  PubMed  Google Scholar 

  23. Kumar B, Gupta SK, Srinivasan BP, Nag TC, Srivastava S, Saxena R, Jha KA (2013) Hesperetin rescues retinal oxidative stress, neuroinflammation and apoptosis in diabetic rats. Microvasc Res 87:65–74

    Article  CAS  PubMed  Google Scholar 

  24. Lambert IH, Pedersen SF, Poulsen KA (2006) Activation of PLA2 isoforms by cell swelling and ischaemia/hypoxia. Acta Physiol (Oxf) 187:75–85

    Article  CAS  Google Scholar 

  25. Lees GJ (1991) Inhibition of sodium-potassium-ATPase: a potentially ubiquitous mechanism contributing to central nervous system neuropathology. Brain Res Rev 16:283–380

    Article  CAS  PubMed  Google Scholar 

  26. Li Y, Holtzclaw LA, Russell JT (2001) Müller cell Ca2+ waves evoked by purinergic receptor agonists in slices of rat retina. J Neurophysiol 85:986–994

    CAS  PubMed  Google Scholar 

  27. Linnertz R, Wurm A, Pannicke T, Krügel K, Hollborn M, Härtig W, Iandiev I, Wiedemann P, Reichenbach A, Bringmann A (2011) Activation of voltage-gated Na+ and Ca2+ channels is required for vesicular release of glutamate from retinal glial cells implicated in cell volume regulation. Neuroscience 188:23–34

    Article  CAS  PubMed  Google Scholar 

  28. Milenkovic I, Weick M, Wiedemann P, Reichenbach A, Bringmann A (2003) P2Y receptor-mediated stimulation of Müller glial cell DNA synthesis: dependence on EGF and PDGF receptor transactivation. Invest Ophthalmol Vis Sci 44:1211–1220

    Article  PubMed  Google Scholar 

  29. Newman EA (2001) Propagation of intercellular calcium waves in retinal astrocytes and Müller cells. J Neurosci 21:2215–2223

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Newman EA (2003) Glial cell inhibition of neurons by release of ATP. J Neurosci 23:1659–1666

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Osborne NN, Álvarez CN, del Olmo Aguado S (2014) Targeting mitochondrial dysfunction as in aging and glaucoma. Drug Discov Today 19:1613–1622

    Article  CAS  PubMed  Google Scholar 

  32. Owada S, Larsson O, Arkhammar P, Katz AI, Chibalin AV, Berggren PO, Bertorello AM (1999) Glucose decreases Na+, K+-ATPase activity in pancreatic β-cells: an effect mediated via Ca2+-independent phospholipase A2 and protein kinase C-dependent phosphorylation of the α-subunit. J Biol Chem 274:2000–2008

    Article  CAS  PubMed  Google Scholar 

  33. Pannicke T, Iandiev I, Uckermann O, Biedermann B, Kutzera F, Wiedemann P, Wolburg H, Reichenbach A, Bringmann A (2004) A potassium channel-linked mechanism of glial cell swelling in the postischemic retina. Mol Cell Neurosci 26:493–502

    Article  CAS  PubMed  Google Scholar 

  34. Reichenbach A, Bringmann A (2015) Purinergic signaling in retinal degeneration and regeneration. Neuropharmacology, (in press)

  35. Rothova A, Suttorp-van Schulten MS, Frits Treffers W, Kijlstra A (1996) Causes and frequency of blindness in patients with intraocular inflammatory disease. Br J Ophthalmol 80:332–336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Staub F, Winkler A, Peters J, Kempski O, Kachel V, Baethmann A (1994) Swelling, acidosis, and irreversible damage of glial cells from exposure to arachidonic acid in vitro. J Cereb Blood Flow Metab 14:1030–1039

    Article  CAS  PubMed  Google Scholar 

  37. Stepinac TK, Chamot SR, Rungger-Brändle E, Ferrez P, Munoz JL, Van Den Bergh H, Riva CE, Pournaras CJ, Wagnieres GA (2005) Light-induced retinal vascular damage by Pd-porphyrin luminescent oxygen probes. Invest Ophthalmol Vis Sci 46:956–966

    Article  PubMed  Google Scholar 

  38. Uckermann O, Vargová L, Ulbricht E, Klaus C, Weick M, Rillich K, Wiedemann P, Reichenbach A, Syková E, Bringmann A (2004) Glutamate-evoked alterations of glial and neuronal cell morphology in the guinea-pig retina. J Neurosci 24:10149–10158

    Article  CAS  PubMed  Google Scholar 

  39. Uckermann O, Wolf A, Kutzera F, Kalisch F, Beck-Sickinger A, Wiedemann P, Reichenbach A, Bringmann A (2006) Glutamate release by neurons evokes a purinergic inhibitory mechanism of osmotic glial cell swelling in the rat retina: activation by neuropeptide Y. J Neurosci Res 83:538–550

    Article  CAS  PubMed  Google Scholar 

  40. Vogler S, Pannicke T, Hollborn M, Grosche A, Busch S, Hoffmann S, Wiedemann P, Reichenbach A, Hammes HP, Bringmann A (2013) Müller cell reactivity in response to photoreceptor degeneration in rats with defective polycystin-2. PLoS One 8:e61631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Vogler S, Grosche A, Pannicke T, Ulbricht E, Wiedemann P, Reichenbach A, Bringmann A (2013) Hypoosmotic and glutamate-induced swelling of bipolar cells in the rat retina: comparison with swelling of Müller glial cells. J Neurochem 126:372–381

    Article  CAS  PubMed  Google Scholar 

  42. Voigt J, Grosche A, Vogler S, Pannicke T, Hollborn M, Kohen L, Wiedemann P, Reichenbach A, Bringmann A (2015) Nonvesicular release of ATP from rat retinal glial (Müller) cells is differentially mediated in response to osmotic stress and glutamate. Neurochem Res 40:651–660

    Article  CAS  PubMed  Google Scholar 

  43. Wurm A, Pannicke T, Wiedemann P, Reichenbach A, Bringmann A (2008) Glial cell-derived glutamate mediates autocrine cell volume regulation in the retina: activation by VEGF. J Neurochem 104:386–399

    CAS  PubMed  Google Scholar 

  44. Wurm A, Lipp S, Pannicke T, Linnertz R, Krügel U, Schulz A, Färber K, Zahn D, Grosse J, Wiedemann P, Chen J, Schöneberg T, Illes P, Reichenbach A, Bringmann A (2010) Endogenous purinergic signaling is required for osmotic volume regulation of retinal glial cells. J Neurochem 112:1261–1272

    Article  CAS  PubMed  Google Scholar 

  45. Zheng W, Watts LT, Holstein DM, Prajapati SI, Keller C, Grass EH, Walter CA, Lechleiter JD (2010) Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mitochondria. PLoS One 5:e14401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zheng W, Talley Watts L, Holstein DM, Wewer J, Lechleiter JD (2013) P2Y1R-initiated, IP3R-dependent stimulation of astrocyte mitochondrial metabolism reduces and partially reverses ischemic neuronal damage in mouse. J Cereb Blood Flow Metab 33:600–611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by grants from the Deutsche Forschungsgemeinschaft (GRK 1097 and RE 849/16-1 to A.R.; PA 615/2-1 to T.P.; GRK 1874 to H.P.H.).

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Authors and Affiliations

  1. Paul Flechsig Institute of Brain Research, University of Leipzig, Leipzig, Germany

    Stefanie Vogler, Thomas Pannicke & Andreas Reichenbach

  2. Department of Ophthalmology and Eye Hospital, University of Leipzig, Liebigstrasse 10-14, 04103, Leipzig, Germany

    Margrit Hollborn, Peter Wiedemann & Andreas Bringmann

  3. 5th Medical Department, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

    Matthias Kolibabka & Hans-Peter Hammes

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  1. Stefanie Vogler
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  2. Thomas Pannicke
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Correspondence to Andreas Bringmann.

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Vogler, S., Pannicke, T., Hollborn, M. et al. Impaired Purinergic Regulation of the Glial (Müller) Cell Volume in the Retina of Transgenic Rats Expressing Defective Polycystin-2. Neurochem Res 41, 1784–1796 (2016). https://doi.org/10.1007/s11064-016-1894-0

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