Hostname: page-component-cd9895bd7-dzt6s Total loading time: 0 Render date: 2024-12-26T00:46:36.830Z Has data issue: false hasContentIssue false
  • English
  • Français

Loss of CD40 attenuates experimental diabetes-induced retinal inflammation but does not protect mice from electroretinogram defects

Published online by Cambridge University Press:  27 June 2017

IVY S. SAMUELS ,
JOSE-ANDRES C. PORTILLO ,
YANLING MIAO ,
TIMOTHY S. KERN  and
CARLOS S. SUBAUSTE
IVY S. SAMUELS
Affiliation:
Research Service, Louis Stokes Cleveland Veterans Administration Medical Center, Cleveland, Ohio 44106 Department of Ophthalmic Research, Cole Eye Institute, Cleveland, Ohio 44195
JOSE-ANDRES C. PORTILLO
Affiliation:
Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106
YANLING MIAO
Affiliation:
Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106
TIMOTHY S. KERN
Affiliation:
Research Service, Louis Stokes Cleveland Veterans Administration Medical Center, Cleveland, Ohio 44106 Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio 44106 Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106
CARLOS S. SUBAUSTE
Affiliation:
Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106 Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio 44106 Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106
Get access Rights & Permissions [Opens in a new window]

Abstract

Chronic low grade inflammation is considered to contribute to the development of experimental diabetic retinopathy (DR). We recently demonstrated that lack of CD40 in mice ameliorates the upregulation of inflammatory molecules in the diabetic retina and prevented capillary degeneration, a hallmark of experimental diabetic retinopathy. Herein, we investigated the contribution of CD40 to diabetes-induced reductions in retinal function via the electroretinogram (ERG) to determine if inflammation plays a role in the development of ERG defects associated with diabetes. We demonstrate that diabetic CD40−/− mice are not protected from reduction to the ERG b-wave despite failing to upregulate inflammatory molecules in the retina. Our data therefore supports the hypothesis that retinal dysfunction found in diabetics occurs independent of the induction of inflammatory processes.

Keywords

Diabetic retinopathyElectroretinogramCD40Inflammation
Type
Research Article
Information
Visual Neuroscience , Volume 34 , 2017 , E009
Copyright
Copyright © Cambridge University Press 2017 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

*

These authors contributed equally to this work.

References

Abu El-Asrar, A.M., Desmet, S., Meersschaert, A., Dralands, L., Missotten, L. & Geboes, K. (2001). Expression of the inducible isoform of nitric oxide synthase in the retinas of human subjects with diabetes mellitus. American Journal of Ophthalmology 132, 551–556.Google Scholar
Antonetti, D.A., Klein, R. & Gardner, T.W. (2012). Diabetic retinopathy. The New England Journal of Medicine 366, 1227–1239.Google Scholar
Arden, G.B., Gunduz, M.K., Kurtenbach, A., Volker, M., Zrenner, E., Gunduz, S.B., Kamis, U., Ozturk, B.T. & Okudan, S. (2010). A preliminary trial to determine whether prevention of dark adaptation affects the course of early diabetic retinopathy. Eye 24, 1149–1155.CrossRefGoogle ScholarPubMed
Arden, G.B., Jyothi, S., Hogg, C.H., Lee, Y.F. & Sivaprasad, S. (2011). Regression of early diabetic macular oedema is associated with prevention of dark adaptation. Eye 25, 1546–1554.Google Scholar
Arden, G.B. & Sivaprasad, S. (2011). Hypoxia and oxidative stress in the causation of diabetic retinopathy. Current Diabetes Reviews 7, 291–304.Google Scholar
Arden, G.B., Wolf, J.E. & Tsang, Y. (1998). Does dark adaptation exacerbate diabetic retinopathy? Evidence and a linking hypothesis. Vision Research 38, 1723–1729.Google Scholar
Aung, M.H., Kim, M.K., Olson, D.E., Thule, P.M. & Pardue, M.T. (2013). Early visual deficits in streptozotocin-induced diabetic long evans rats. Investigative Ophthalmology & Visual Science 54, 1370–1377.CrossRefGoogle ScholarPubMed
Barber, A.J. (2003). A new view of diabetic retinopathy: A neurodegenerative disease of the eye. Progress in Neuro-Psychopharmacology & Biological Psychiatry 27, 283–290.CrossRefGoogle ScholarPubMed
Barber, A.J., Lieth, E., Khin, S.A., Antonetti, D.A., Buchanan, A.G. & Gardner, T.W. (1998). Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. The Journal of Clinical Investigation 102, 783–791.CrossRefGoogle ScholarPubMed
Barile, G.R., Pachydaki, S.I., Tari, S.R., Lee, S.E., Donmoyer, C.M., Ma, W., Rong, L.L., Buciarelli, L.G., Wendt, T., Horig, H., Hudson, B.I., Qu, W., Weinberg, A.D., Yan, S.F. & Schmidt, A.M. (2005). The RAGE axis in early diabetic retinopathy. Investigative Ophthalmology & Visual Science 46, 2916–2924.CrossRefGoogle ScholarPubMed
Bearse, M.A. Jr., Adams, A.J., Han, Y., Schneck, M.E., Ng, J., Bronson-Castain, K. & Barez, S. (2006). A multifocal electroretinogram model predicting the development of diabetic retinopathy. Progress in Retinal and Eye Research 25, 425–448.Google Scholar
Bogdanov, P., Corraliza, L., Villena, J.A., Carvalho, A.R., Garcia-Arumi, J., Ramos, D., Ruberte, J., Simo, R. & Hernandez, C. (2014). The db/db mouse: A useful model for the study of diabetic retinal neurodegeneration. PLoS One 9, e97302.Google Scholar
Boynton, G.E., Stem, M.S., Kwark, L., Jackson, G.R., Farsiu, S. & Gardner, T.W. (2015). Multimodal characterization of proliferative diabetic retinopathy reveals alterations in outer retinal function and structure. Ophthalmology 122, 957–967.CrossRefGoogle ScholarPubMed
Bresnick, G.H., Korth, K., Groo, A. & Palta, M. (1984). Electroretinographic oscillatory potentials predict progression of diabetic retinopathy. Preliminary report. Archives of Ophthalmology 102, 1307–1311.Google Scholar
Bronson-Castain, K.W., Bearse, M.A. Jr., Neuville, J., Jonasdottir, S., King-Hooper, B., Barez, S., Schneck, M.E. & Adams, A.J. (2012). Early neural and vascular changes in the adolescent type 1 and type 2 diabetic retina. Retina 32, 92–102.Google Scholar
Di Leo, M.A., Caputo, S., Falsini, B., Porciatti, V., Greco, A.V. & Ghirlanda, G. (1994). Presence and further development of retinal dysfunction after 3-year follow up in IDDM patients without angiographically documented vasculopathy. Diabetologia 37, 911–916.Google Scholar
Di Leo, M.A., Falsini, B., Caputo, S., Ghirlanda, G., Porciatti, V. & Greco, A.V. (1990). Spatial frequency-selective losses with pattern electroretinogram in type 1 (insulin-dependent) diabetic patients without retinopathy. Diabetologia 33, 726–730.CrossRefGoogle ScholarPubMed
Du, Y., Smith, M.A., Miller, C.M. & Kern, T.S. (2002). Diabetes-induced nitrative stress in the retina, and correction by aminoguanidine. Journal of Neurochemistry 80, 771–779.Google Scholar
Hancock, H.A. & Kraft, T.W. (2004). Oscillatory potential analysis and ERGs of normal and diabetic rats. Investigative Ophthalmology & Visual Science 45, 1002–1008.Google Scholar
Huang, H., Gandhi, J.K., Zhong, X., Wei, Y., Gong, J., Duh, E.J. & Vinores, S.A. (2011). TNF-a is required for late BRB breakdown in diabetic retinopathy, and its inhibition prevents leukostasis and protects vessels and neurons from apoptosis. Investigative Ophthalmology & Visual Science 52, 1336–1344.Google Scholar
Jackson, G.R. & Barber, A.J. (2010). Visual dysfunction associated with diabetic retinopathy. Current Diabetes Reports 10, 380–384.CrossRefGoogle ScholarPubMed
Joussen, A.M., Doehmen, S., Le, M.L., Koizumi, K., Radetzky, S., Krohne, T.U., Poulaki, V., Semkova, I. & Kociok, N. (2009). TNF-α mediated apoptosis plays an important role in the development of early diabetic retinopathy and long-term histopathological alterations. Molecular Vision 15, 1418–1428.Google Scholar
Joussen, A.M., Poulaki, V., Le, M.L., Koizumi, K., Esser, C., Janicki, H., Schraermeyer, U., Kociok, N., Fauser, S., Kirchlof, B., Kern, T.S. & Adamis, A.P. (2004). A central role for inflammation in the pathogenesis of diabetic retinopathy. FASEB Journal 18, 1450–1452.CrossRefGoogle ScholarPubMed
Kawasaki, K., Yonemura, K., Yokogawa, Y., Saito, N. & Kawakita, S. (1986). Correlation between ERG oscillatory potential and psychophysical contrast sensitivity in diabetes. Documenta Ophthalmologica: Advances in Ophthalmology 64, 209–215.CrossRefGoogle ScholarPubMed
Krady, J.K., Basu, A., Allen, C.M., Xu, Y., LaNoue, K.F., Gardner, T.W. & Levison, S.W. (2005). Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy. Diabetes 54, 1559–1565.Google Scholar
Kur, J., Burian, M.A. & Newman, E.A. (2016). Light adaptation does not prevent early retinal abnormalities in diabetic rats. Scientific Reports 6, 21075.Google Scholar
Lai, A.K. & Lo, A.C. (2013). Animal models of diabetic retinopathy: Summary and comparison. Journal of Diabetes Research 2013, 106594.Google Scholar
Lakhani, E., Wright, T., Abdolell, M. & Westall, C. (2010). Multifocal ERG defects associated with insufficient long-term glycemic control in adolescents with type 1 diabetes. Investigative Ophthalmology & Visual Science 51, 5297–5303.Google Scholar
Laron, M., Bearse, M.A. Jr., Bronson-Castain, K., Jonasdottir, S., King-Hooper, B., Barez, S., Schneck, M.E. & Adams, A.J. (2012). Association between local neuroretinal function and control of adolescent type 1 diabetes. Investigative Ophthalmology & Visual Science 53, 7071–7076.Google Scholar
Leal, E.C., Manivannan, A., Hosoya, K-I., Terasaki, T., Cunha-Vaz, J., Ambrosio, A.F. & Forrester, J.V. (2007). Inducible nitric oxide synthase isoform is a key mediator of leukostasis and blood-retinal barrier breakdown in diabetic retinopathy. Investigative Ophthalmology & Visual Science 48, 5257–5265.Google Scholar
Lee, C.A., Li, G., Patel, M.D., Petrash, J.M., Benetz, B.A., Veenstra, A., Amengual, J., von Lintig, J., Burant, C.J., Tang, J. & Kern, T.S. (2014). Diabetes-induced impairment in visual function in mice: Contributions of p38 MAPK, RAGE, leukocytes, and aldose reductase. Investigative Ophthalmology & Visual Science 55, 2904–2910.Google Scholar
Li, Q., Zemel, E., Miller, B. & Perlman, I. (2002). Early retinal damage in experimental diabetes: Electroretinographical and morphological observations. Experimental Eye Research 74, 615–625.Google Scholar
Liu, H., Tang, J., Du, Y., Saadane, A., Tonade, D., Samuels, I., Veenstra, A., Palczewski, K. & Kern, T.S. (2016). Photoreceptor cells influence retinal vascular degeneration in mouse models of retinal degeneration and diabetes. Investigative Ophthalmology & Visual Science 57, 4272–4281.CrossRefGoogle ScholarPubMed
Liu, H., Tang, J., Lee, C.A. & Kern, T.S. (2015). Metanx and early stages of diabetic retinopathy. Investigative Ophthalmology & Visual Science 56, 647–653.Google Scholar
McLeod, D.S., Lefer, D.J., Merges, C. & Lutty, G.A. (1995). Enhanced expression of intracellular adhesion molecule-1 and P-selectin in the diabetic human retina and choroid. American Journal of Pathology 147, 642–653.Google Scholar
Ozawa, Y., Kurihara, T., Sasaki, M., Ban, N., Yuki, K., Kubota, S. & Tsubota, K. (2011). Neural degeneration in the retina of the streptozotocin-induced type 1 diabetes model. Experimental Diabetes Research 2011, 108328.Google Scholar
Pardue, M.T., Barnes, C.S., Kim, M.K., Aung, M.H., Amarnath, R., Olson, D.E. & Thule, P.M. (2014a). Rodent hyperglycemia-induced inner retinal deficits are mirrored in human diabetes. Translational Vision Science & Technology 3, 6.CrossRefGoogle ScholarPubMed
Pardue, M.T., Ciavatta, V.T. & Hetling, J.R. (2014b). Neuroprotective effects of low level electrical stimulation therapy on retinal degeneration. Advances in Experimental Medicine and Biology 801, 845–851.Google Scholar
Pescosolido, N., Barbato, A., Stefanucci, A. & Buomprisco, G. (2015). Role of electrophysiology in the early diagnosis and follow-up of diabetic retinopathy. Journal of Diabetes Research 2015, 319692.Google Scholar
Phipps, J.A., Fletcher, E.L. & Vingrys, A.J. (2004). Paired-flash identification of rod and cone dysfunction in the diabetic rat. Investigative Ophthalmology & Visual Science 45, 4592–4600.Google Scholar
Phipps, J.A., Yee, P., Fletcher, E.L. & Vingrys, A.J. (2006). Rod photoreceptor dysfunction in diabetes: Activation, deactivation, and dark adaptation. Investigative Ophthalmology & Visual Science 47, 3187–3194.CrossRefGoogle ScholarPubMed
Portillo, J.A., Greene, J.A., Okenka, G., Miao, Y., Sheibani, N., Kern, T.S. & Subauste, C.S. (2014a). CD40 promotes the development of early diabetic retinopathy in mice. Diabetologia 57, 2222–2231.CrossRefGoogle ScholarPubMed
Portillo, J.A., Okenka, G., Kern, T.S. & Subauste, C.S. (2009). Identification of primary retinal cells and ex vivo detection of proinflammatory molecules using flow cytometry. Molecular Vision 15, 1383–1389.Google Scholar
Portillo, J.A., Schwartz, I., Zarini, S., Bapputty, R., Kern, T.S., Gubitosi-Klug, R.A., Murphy, R.C., Subauste, M.C. & Subauste, C.S. (2014b). Proinflammatory responses induced by CD40 in retinal endothelial and Muller cells are inhibited by blocking CD40-Traf2,3 or CD40-Traf6 signaling. Investigative Ophthalmology & Visual Science 55, 8590–8597.Google Scholar
Portillo, J.C., Lopez Corcino, Y., Miao, Y., Tang, J., Sheibani, N., Kern, T.S., Dubyak, G.R. & Subauste, C.S. (2017). CD40 in retinal muller cells induces P2X7-dependent cytokine expression in macrophages/microglia in diabetic mice and development of early experimental diabetic retinopathy. Diabetes 66, 483–493.Google Scholar
Rajagopal, R., Bligard, G.W., Zhang, S., Yin, L., Lukasiewicz, P. & Semenkovich, C.F. (2016). Functional deficits precede structural lesions in mice with high-fat diet-induced diabetic retinopathy. Diabetes 65, 1072–1084.Google Scholar
Roy, M.S., Gunkel, R.D. & Podgor, M.J. (1986). Color vision defects in early diabetic retinopathy. Archives of Ophthalmology 104, 225–228.CrossRefGoogle ScholarPubMed
Roy, S., Kern, T.S., Song, B. & Stuebe, C. (2017). Mechanistic insights into pathological changes in the diabetic retina: Implications for targeting diabetic retinopathy. American Journal of Pathology 187, 9–19.Google Scholar
Saliba, A., Du, Y., Liu, H., Patel, S., Roberts, R., Berkowitz, B.A. & Kern, T.S. (2015). Photobiomodulation mitigates diabetes-induced retinopathy by direct and indirect mechanisms: Evidence from intervention studies in pigmented mice. PLoS One 10, e0139003.Google Scholar
Samuels, I.S., Bell, B.A., Pereira, A., Saxon, J. & Peachey, N.S. (2015). Early retinal pigment epithelium dysfunction is concomitant with hyperglycemia in mouse models of type 1 and type 2 diabetes. Journal of Neurophysiology 113, 1085–1099.Google Scholar
Samuels, I.S., Lee, C.A., Petrash, J.M., Peachey, N.S. & Kern, T.S. (2012). Exclusion of aldose reductase as a mediator of ERG deficits in a mouse model of diabetic eye disease. Visual Neuroscience 29, 267–274.CrossRefGoogle Scholar
Samuels, I.S., Sturgill, G.M., Grossman, G.H., Rayborn, M.E., Hollyfield, J.G. & Peachey, N.S. (2010). Light-evoked responses of the retinal pigment epithelium: Changes accompanying photoreceptor loss in the mouse. Journal of Neurophysiology 104, 391–402.Google Scholar
Schneck, M.E., Fortune, B. & Adams, A.J. (2000). The fast oscillation of the electrooculogram reveals sensitivity of the human outer retina/retinal pigment epithelium to glucose level. Vision Research 40, 3447–3453.Google Scholar
Shinoda, K., Rejdak, R., Schuettauf, F., Blatsios, G., Volker, M., Tanimoto, N., Olcay, T., Gekeler, F., Lehaci, C., Naskar, R., Zagorski, Z. & Zrenner, E. (2007). Early electroretinographic features of streptozotocin-induced diabetic retinopathy. Clinical & Experimental Ophthalmology 35, 847–854.Google Scholar
Simo, R., Hernandez, C. & European Consortium for the Early Treatment of Diabetic Retinopathy (2012). Neurodegeneration is an early event in diabetic retinopathy: Therapeutic implications. The British Journal of Ophthalmology 96, 1285–1290.Google Scholar
Tan, J., Town, T., Mori, T., Obregon, D., Wu, Y., DelleDonne, A., Rojiani, A., Crawford, F., Flavell, R.A. & Mullan, M. (2002). CD40 is expressed and functional on neuronal cells. The EMBO Journal 21, 643–652.Google Scholar
Tang, J., Du, Y., Lee, C.A., Talahalli, R., Eells, J.T. & Kern, T.S. (2013a). Low-intensity far-red light inhibits early lesions that contribute to diabetic retinopathy: In vivo and in vitro . Investigative Ophthalmology & Visual Science 54, 3681–3690.Google Scholar
Tang, J., Du, Y., Petrash, J.M., Sheibani, N. & Kern, T.S. (2013b). Deletion of aldose reductase from mice inhibits diabetes-induced retinal capillary degeneration and superoxide generation. PLoS One 8, e62081.Google Scholar
Tang, J. & Kern, T.S. (2011). Inflammation in diabetic retinopathy. Progress in Retinal and Eye Research 30, 343–358.Google Scholar
Tonade, D., Liu, H. & Kern, T.S. (2016). Photoreceptor cells produce inflammatory mediators that contribute to endothelial cell death in diabetes. Investigative Ophthalmology & Visual Science 57, 4264–4271.Google Scholar
Tzekov, R. & Arden, G.B. (1999). The electroretinogram in diabetic retinopathy. Survey of Ophthalmology 44, 53–60.Google Scholar
Vincent, J.A. & Mohr, S. (2007). Inhibition of caspase-1/interleukin-1b signaling prevents degeneration of retinal capillaries in diabetes and galactosemia. Diabetes 56, 224–230.Google Scholar
Wachtmeister, L. (1998). Oscillatory potentials in the retina: What do they reveal. Progress in Retinal and Eye Research 17, 485–521.Google Scholar
Yang, L-P., Sun, H-L., Wu, L-M., Guo, X-J., Dou, H-L., Tso, M.O.M., Zhao, L. & Li, S-M. (2009). Baicalein reduces inflammatory process in a rodent model of diabetic retinopathy. Investigative Ophthalmology & Visual Science, 50, 2319–2327.Google Scholar
Yonemura, D., Aoki, T. & Tsuzuki, K. (1962). Electroretinogram in diabetic retinopathy. Archives of Ophthalmology 68, 19–24.Google Scholar
Yu, Y., Chen, H. & Su, S.B. (2015). Neuroinflammatory responses in diabetic retinopathy. Journal of Neuroinflammation 12, 141.CrossRefGoogle ScholarPubMed
Zheng, L., Du, Y., Miller, C., Gubitosi-Klug, R.A., Kern, T.S., Ball, S. & Berkowitz, B.A. (2007a). Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes. Diabetologia 50, 1987–1996.Google Scholar
Zheng, L., Howell, S.J., Hatala, D.A., Huang, K. & Kern, T.S. (2007b). Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy. Diabetes 56, 337–345.Google Scholar