Hostname: page-component-8448b6f56d-jr42d Total loading time: 0 Render date: 2024-04-19T11:47:56.944Z Has data issue: false hasContentIssue false
  • English
  • Français

Exclusion of aldose reductase as a mediator of ERG deficits in a mouse model of diabetic eye disease

Published online by Cambridge University Press:  29 October 2012

IVY S. SAMUELS ,
CHIEH-ALLEN LEE ,
J. MARK PETRASH ,
NEAL S. PEACHEY  and
TIMOTHY S. KERN
IVY S. SAMUELS*
Affiliation:
Research Service, Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
CHIEH-ALLEN LEE
Affiliation:
Department of Medicine, Case Western Reserve University, Cleveland, Ohio
J. MARK PETRASH
Affiliation:
Department of Ophthalmology, University of Colorado, Denver, Colorado
NEAL S. PEACHEY
Affiliation:
Research Service, Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, Ohio
TIMOTHY S. KERN
Affiliation:
Research Service, Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio Department of Medicine, Case Western Reserve University, Cleveland, Ohio
*
*Address correspondence and reprint requests to: Ivy S. Samuels, Research Service, Louis Stokes Cleveland VA Medical Center, 151W, 10701 East Boulevard, Cleveland, OH 44106. E-mail: Ivy.Samuels@va.gov
Get access Rights & Permissions [Opens in a new window]

Abstract

Streptozotocin (STZ)-induced diabetes is associated with reductions in the electrical response of the outer retina and retinal pigment epithelium (RPE) to light. Aldose reductase (AR) is the first enzyme required in the polyol-mediated metabolism of glucose, and AR inhibitors have been shown to improve diabetes-induced electroretinogram (ERG) defects. Here, we used control and AR−/− mice to determine if genetic inactivation of this enzyme likewise inhibits retinal electrophysiological defects observed in a mouse model of type 1 diabetes. STZ was used to induce hyperglycemia and type 1 diabetes. Diabetic and age-matched nondiabetic controls of each genotype were maintained for 22 weeks, after which ERGs were used to measure the light-evoked components of the RPE (dc-ERG) and the neural retina (a-wave, b-wave). In comparison to their nondiabetic controls, wildtype (WT) and AR−/− diabetic mice displayed significant decreases in the c-wave, fast oscillation, and off response components of the dc-ERG but not in the light peak response. Nondiabetic AR−/− mice displayed larger ERG component amplitudes than did nondiabetic WT mice; however, the amplitude of dc-ERG components in diabetic AR−/− animals were similar to WT diabetics. ERG a-wave amplitudes were not reduced in either diabetic group, but b-wave amplitudes were lower in WT and AR−/−diabetic mice. These findings demonstrate that the light-induced responses of the RPE and outer retina are disrupted in diabetic mice, but these defects are not due to photoreceptor dysfunction, nor are they ameliorated by deletion of AR. This latter finding suggests that benefits observed in other studies utilizing pharmacological inhibitors of AR might have been secondary to off-target effects of the drugs.

Keywords

ElectroretinogramAldose reductaseDiabetesRetinal pigment epitheliumDiabetic retinopathyc-waveOuter retina
Type
Review Articles
Information
Visual Neuroscience , Volume 29 , Issue 6 , November 2012 , pp. 267 - 274
Copyright
Copyright © Cambridge University Press 2012

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.)

References

Aizu, Y., Katayama, H., Takahama, S., Hu, J., Nakagawa, H. & Oyanagi, K. (2003). Topical instillation of ciliary neurotrophic factor inhibits retinal degeneration in streptozotocin-induced diabetic rats. Neuroreport 14, 2067–2071.CrossRefGoogle ScholarPubMed
Alvarez, Y., Chen, K., Reynolds, A.L., Waghorne, N., O’Connor, J.J. & Kennedy, B.N. (2010). Predominant cone photoreceptor dysfunction in a hyperglycaemic model of non-proliferative diabetic retinopathy. Disease Models and Mechanisms 3, 236–245.CrossRefGoogle Scholar
Arden, G.B. & Constable, P.A. (2006). The electro-oculogram. Progress in Retinal and Eye Research 25, 207–248.CrossRefGoogle ScholarPubMed
Arnal, E., Miranda, M., Johnsen-Soriano, S., Alvarez-Nolting, R., Diaz-Llopis, M., Araiz, J., Cervera, E., Bosch-Morell, F. & Romero, F.J. (2009). Beneficial effect of docosahexanoic acid and lutein on retinal structural, metabolic, and functional abnormalities in diabetic rats. Current Eye Research 34, 928–938.CrossRefGoogle ScholarPubMed
Ashizawa, N., Yoshida, M., Sugiyama, Y., Akaike, N., Ohbayashi, S., Aotsuka, T., Abe, N., Fukushima, K. & Matsuura, A. (1997). Effects of a novel potent aldose reductase inhibitor, GP-1447, on aldose reductase activity in vitro and on diabetic neuropathy and cataract formation in rats. Japanese Journal of Pharmacology 73, 133–144.CrossRefGoogle ScholarPubMed
Barile, G.R., Rachydaki, 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 and Visual Science 46, 2916–2924.CrossRefGoogle ScholarPubMed
Barski, O.A., Tipparaju, S.M. & Bhatnagar, A. (2008). The aldo-keto reductase superfamily and its role in drug metabolism and detoxification. Drug Metabolism Reviews 40, 553–624.CrossRefGoogle ScholarPubMed
Biersdorf, W.R., Malone, J.I., Pavan, P.R. & Lowitt, S. (1988). Cone electroretinograms and visual acuities of diabetic patients on sorbinil treatment. Documenta Ophthalmologica 69, 247–254.CrossRefGoogle ScholarPubMed
Biro, K., Palhalmi, J., Toth, A.J., Kukorelli, T. & Juhasz, G. (1998). Bimoclomol improves early electrophysiological signs of retinopathy in diabetic rats. Neuroreport 9, 2029–2033.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.CrossRefGoogle ScholarPubMed
Bresnick, G.H. & Palta, M. (1987). Oscillatory potential amplitudes. Relation to severity of diabetic retinopathy. Archives of Ophthalmology 105, 929–933.CrossRefGoogle ScholarPubMed
Bui, B.V., Armitage, J.A., Tolcos, M., Cooper, M.E. & Vingrys, A.J. (2003). ACE inhibition salvages the visual loss caused by diabetes. Diabetologia 46, 401–408.CrossRefGoogle ScholarPubMed
Centers for Disease Control and Prevention. (2011). National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention.Google Scholar
Coupland, S.G. (1987). A comparison of oscillatory potential and pattern electroretinogram measures in diabetic retinopathy. Documenta Ophthalmologica 66, 207–218.CrossRefGoogle ScholarPubMed
Diabetes Control and Complications Trial Research Group. (1993). The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The New England Journal of Medicine 329, 977–986.CrossRefGoogle Scholar
Fujii, S., Gallemore, R.P., Hughes, B.A. & Steinberg, R.H. (1992). Direct evidence for a basolateral membrane Cl- conductance in toad retinal pigment epithelium. The American Journal of Physiology 262, C374–383.CrossRefGoogle ScholarPubMed
Funada, M., Okamoto, I., Fujinaga, Y. & Yamana, T. (1987). Effects of aldose reductase inhibitor (M79175) on ERG oscillatory potential abnormalities in streptozotocin fructose-induced diabetes in rats. Japanese Journal of Ophthalmology 31, 305–314.Google ScholarPubMed
Gallemore, R.P. & Steinberg, R.H. (1989). Effects of DIDS on the chick retinal pigment epithelium. II. Mechanism of the light peak and other responses originating at the basal membrane. The Journal of Neuroscience 9, 1977–1984.CrossRefGoogle ScholarPubMed
Gallemore, R.P. & Steinberg, R.H. (1993). Light-evoked modulation of basolateral membrane Cl- conductance in chick retinal pigment epithelium: The light peak and fast oscillation. Journal of Neurophysiology 70, 1669–1680.CrossRefGoogle ScholarPubMed
Griff, E.R. & Steinberg, R.H. (1984). Changes in apical [K+] produce delayed basal membrane responses of the retinal pigment epithelium in the gecko. The Journal of General Physiology 83, 193–211.CrossRefGoogle ScholarPubMed
Hancock, H.A. & Kraft, T.W. (2004). Oscillatory potential analysis and ERGs of normal and diabetic rats. Investigative Ophthalmology and Visual Science 45, 1002–1008.CrossRefGoogle ScholarPubMed
Hardy, K.J., Fisher, C., Heath, P., Foster, D.H. & Scarpello, J.H. (1995). Comparison of colour discrimination and electroretinography in evaluation of visual pathway dysfunction in aretinopathic IDDM patients. The British Journal of Ophthalmology 79, 35–37.CrossRefGoogle ScholarPubMed
Hers, H.G. (1962). [Increase of activity of glucose-6-phosphatase in intolerance to fructose]. Revue Internationale d’Hepatologie 12, 777–782.Google ScholarPubMed
Ho, H.T., Chung, S.K., Law, J.W., Ko, B.C., Tam, S.C., Brooks, H.L., Knepper, M.A. & Chung, S.S. (2000). Aldose reductase-deficient mice develop nephrogenic diabetes insipidus. Molecular and Cellular Biology 20, 5840–5846.CrossRefGoogle ScholarPubMed
Holopigian, K., Seiple, W., Lorenzo, M. & Carr, R. (1992). A comparison of photopic and scotopic electroretinographic changes in early diabetic retinopathy. Investigative Ophthalmology and Visual Science 33, 2773–2780.Google ScholarPubMed
Hotta, N. (1995). New approaches for treatment in diabetes: Aldose reductase inhibitors. Biomedicine and Pharmacotherapy 49, 232–243.CrossRefGoogle ScholarPubMed
Hotta, N., Koh, N., Sakakibara, F., Nakamura, J., Hamada, Y., Hara, T., Fukasawa, H., Kakuta, H. & Sakamoto, N. (1996). Effect of propionyl-L-carnitine on oscillatory potentials in electroretinogram in streptozotocin-diabetic rats. European Journal of Pharmacology 311, 199–206.CrossRefGoogle ScholarPubMed
Hotta, N., Koh, N., Sakakibara, F., Nakamura, J., Hamada, Y., Hara, T., Takeuchi, N., Inukai, S., Kasama, N., Fukasawa, H. & Kakuta, H. (1995 a). An aldose reductase inhibitor, TAT, prevents electroretinographic abnormalities and ADP-induced hyperaggregability in streptozotocin-induced diabetic rats. European Journal of Clinical Investigation 25, 948–954.CrossRefGoogle ScholarPubMed
Hotta, N., Koh, N., Sakakibara, F., Nakamura, J., Hamada, Y., Naruse, K., Sasaki, H., Mizuno, K., Matsubara, A., Kakuta, H., Fukasawa, H. & Sakamoto, N. (1995 b). Effect of an aldose reductase inhibitor, SNK-860, on deficits in the electroretinogram of diabetic rats. Experimental Physiology 80, 981–989.CrossRefGoogle ScholarPubMed
Hotta, N., Koh, N., Sakakibara, F., Nakamura, J., Hara, T., Hamada, Y., Fukasawa, H., Kakuta, H. & Sakamoto, N. (1997). Effect of an aldose reductase inhibitor on abnormalities of electroretinogram and vascular factors in diabetic rats. European Journal of Pharmacology 326, 45–51.CrossRefGoogle ScholarPubMed
Johnsen-Soriano, S., Garcia-Pous, M., Arnal, E., Sancho-Tello, M., Garcia-Delpech, S., Miranda, M., Bosch-Morell, F., Diaz-Llopis, M., Navea, A. & Romero, F.J. (2008). Early lipoic acid intake protects retina of diabetic mice. Free Radical Research 42, 613–617.CrossRefGoogle ScholarPubMed
Juen, S. & Kieselbach, G.F. (1990). Electrophysiological changes in juvenile diabetics without retinopathy. Archives of Ophthalmology 108, 372–375.CrossRefGoogle ScholarPubMed
Kofuji, P., Ceelen, P., Zahs, K.R., Surbeck, L.W., Lester, H.A. & Newman, E.A. (2000). Genetic inactivation of an inwardly rectifying potassium channel (Kir4.1 subunit) in mice: Phenotypic impact in retina. The Journal of Neuroscience 20, 5733–5740.CrossRefGoogle ScholarPubMed
Levin, R.D., Kwaan, H.C., Dobbie, J.G., Fetkenhour, C.L., Traisman, H.S. & Kramer, C. (1982). Studies of retinopathy and the plasma co-factor of platelet hyperaggregation in type 1 (insulin-dependent) diabetic children. Diabetologia 22, 445–449.CrossRefGoogle ScholarPubMed
Linsenmeier, R.A. & Steinberg, R.H. (1982). Origin and sensitivity of the light peak in the intact cat eye. The Journal of Physiology 331, 653–673.CrossRefGoogle ScholarPubMed
Lovasik, J.V. & Spafford, M.M. (1988). An electrophysiological investigation of visual function in juvenile insulin-dependent diabetes mellitus. American Journal of Optometry and Physiological Optics 65, 236–253.CrossRefGoogle ScholarPubMed
Lowitt, S., Malone, J.I., Salem, A., Kozak, W.M. & Orfalian, Z. (1993). Acetyl-L-carnitine corrects electroretinographic deficits in experimental diabetes. Diabetes 42, 1115–1118.CrossRefGoogle ScholarPubMed
MacGregor, L.C. & Matschinsky, F.M. (1985). Treatment with aldose reductase inhibitor or with myo-inositol arrests deterioration of the electroretinogram of diabetic rats. The Journal of Clinical Investigation 76, 887–889.CrossRefGoogle ScholarPubMed
MacGregor, L.C. & Matschinsky, F.M. (1986). Experimental diabetes mellitus impairs the function of the retinal pigmented epithelium. Metabolism: Clinical and Experimental 35, 28–34.CrossRefGoogle ScholarPubMed
MacGregor, L.C., Rosecan, L.R., Laties, A.M. & Matschinsky, F.M. (1986). Altered retinal metabolism in diabetes. I. Microanalysis of lipid, glucose, sorbitol, and myo-inositol in the choroid and in the individual layers of the rabbit retina. The Journal of Biological Chemistry 261, 4046–4051.CrossRefGoogle ScholarPubMed
Matsui, T., Nakamura, Y., Ishikawa, H., Matsuura, A. & Kobayashi, F. (1994). Pharmacological profiles of a novel aldose reductase inhibitor, SPR-210, and its effects on streptozotocin-induced diabetic rats. Japanese Journal of Pharmacology 64, 115–124.CrossRefGoogle ScholarPubMed
Nakamura, J., Kato, K., Hamada, Y., Nakayama, M., Chaya, S., Nakashima, E., Naruse, K., Kasuya, Y., Mizubayashi, R., Miwa, K., Yasuda, Y., Kamiya, H., Ienaga, K., Sakakibara, F., Koh, N. & Hotta, N. (1999). A protein kinase C-beta-selective inhibitor ameliorates neural dysfunction in streptozotocin-induced diabetic rats. Diabetes 48, 2090–2095.CrossRefGoogle ScholarPubMed
Nanasi, P.P. & Jednakovits, A. (2001). Multilateral in vivo and in vitro protective effects of the novel heat shock protein coinducer, bimoclomol: Results of preclinical studies. Cardiovascular Drug Reviews 19, 133–151.CrossRefGoogle ScholarPubMed
Oakley, B. II & Green, D.G. (1976). Correlation of light-induced changes in retinal extracellular potassium concentration with c-wave of the electroretinogram. Journal of Neurophysiology 39, 1117–1133.CrossRefGoogle ScholarPubMed
Pautler, E.L. & Ennis, S.R. (1980). The effect of induced diabetes on the electroretinogram components of the pigmented rat. Investigative Ophthalmology and Visual Science 19, 702–705.Google ScholarPubMed
Phipps, J.A. & Feener, E.P. (2008). The kallikrein-kinin system in diabetic retinopathy: Lessons for the kidney. Kidney International 73, 1114–1119.CrossRefGoogle ScholarPubMed
Phipps, J.A., Fletcher, E.L. & Vingrys, A.J. (2004). Paired-flash identification of rod and cone dysfunction in the diabetic rat. Investigative Ophthalmology and Visual Science 45, 4592–4600.CrossRefGoogle ScholarPubMed
Phipps, J.A., Yee, P., Fletcher, E.L. & Vingrys, A.J. (2006). Rod photoreceptor dysfunction in diabetes: Activation, deactivation, and dark adaptation. Investigative Ophthalmology and Visual Science 47, 3187–3194.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Schmidt, R. & Steinberg, R.H. (1971). Rod-dependent intracellular responses to light recorded from the pigment epithelium of the cat retina. The Journal of Physiology 217, 71–91.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Schneck, M.E., Shupenko, L. & Adams, A.J. (2008). The fast oscillation of the EOG in diabetes with and without mild retinopathy. Documenta Ophthalmologica 116, 231–236.CrossRefGoogle ScholarPubMed
Shirao, Y. & Kawasaki, K. (1998). Electrical responses from diabetic retina. Progress in Retinal and Eye Research 17, 59–76.CrossRefGoogle ScholarPubMed
Simo, R. & Hernandez, C. (2009). Advances in the medical treatment of diabetic retinopathy. Diabetes Care 32, 1556–1562.CrossRefGoogle ScholarPubMed
Steinberg, R.H. (1985). Interactions between the retinal pigment epithelium and the neural retina. Documenta Ophthalmologica 60, 327–346.CrossRefGoogle ScholarPubMed
Steinberg, R.H. & Miller, S. (1973). Aspects of electrolyte transport in frog pigment epithelium. Experimental Eye Research 16, 365–372.CrossRefGoogle ScholarPubMed
Steinberg, R.H., Schmidt, R. & Brown, K.T. (1970). Intracellular responses to light from cat pigment epithelium: Origin of the electroretinogram c-wave. Nature 227, 728–730.CrossRefGoogle ScholarPubMed
Strauss, O. (2005). The retinal pigment epithelium in visual function. Physiological Reviews 85, 845–881.CrossRefGoogle ScholarPubMed
Tzekov, R. & Arden, G.B. (1999). The electroretinogram in diabetic retinopathy. Survey of Ophthalmology 44, 53–60.CrossRefGoogle ScholarPubMed
Villarroel, M., Garcia-Ramirez, M., Corraliza, L., Hernandez, C. & Simo, R. (2009 a). Effects of high glucose concentration on the barrier function and the expression of tight junction proteins in human retinal pigment epithelial cells. Experimental Eye Research 89, 913–920.CrossRefGoogle ScholarPubMed
Villarroel, M., Garcia-Ramirez, M., Corraliza, L., Hernandez, C. & Simo, R. (2009 b). High glucose concentration leads to differential expression of tight junction proteins in human retinal pigment epithelial cells. Endocrinologia y Nutricion 56, 53–58.CrossRefGoogle ScholarPubMed
Vinores, S.A., Derevjanik, N.L., Ozaki, H., Okamoto, N. & Campochiaro, P.A. (1999). Cellular mechanisms of blood-retinal barrier dysfunction in macular edema. Documenta Ophthalmologica 97, 217–228.CrossRefGoogle ScholarPubMed
Wang, J., Xu, X., Elliott, M.H., Zhu, M. & Le, Y.Z. (2010). Muller cell-derived VEGF is essential for diabetes-induced retinal inflammation and vascular leakage. Diabetes 59, 2297–2305.CrossRefGoogle ScholarPubMed
Witkovsky, P., Dudek, F.E. & Ripps, H. (1975). Slow PIII component of the carp electroretinogram. The Journal of General Physiology 65, 119–134.CrossRefGoogle ScholarPubMed
Wong, V.H., Bui, B.V. & Vingrys, A.J. (2011). Clinical and experimental links between diabetes and glaucoma. Clinical and Experimental Optometry 94, 4–23.CrossRefGoogle ScholarPubMed
Wu, J., Marmorstein, A.D., Kofuji, P. & Peachey, N.S. (2004 a). Contribution of Kir4.1 to the mouse electroretinogram. Molecular Vision 10, 650–654.Google Scholar
Wu, J., Peachey, N.S. & Marmorstein, A.D. (2004 b). Light-evoked responses of the mouse retinal pigment epithelium. Journal of Neurophysiology 91, 1134–1142.CrossRefGoogle ScholarPubMed
Xu, H.Z. & Le, Y.Z. (2011). Significance of outer blood-retina barrier breakdown in diabetes and ischemia. Investigative Ophthalmology and Visual Science 52, 2160–2164.CrossRefGoogle ScholarPubMed
Xu, H.-Z., Song, Z., Fu, S., Zhu, M. & Le, Y.-Z. (2011). RPE barrier breakdown in diabetic retinopathy: Seeing is believing. Journal of Ocular Biology, Diseases, and Informatics 4, 83–92.CrossRefGoogle ScholarPubMed
Yee, P., Weymouth, A.E., Fletcher, E.L. & Vingrys, A.J. (2010). A role for omega-3 polyunsaturated fatty acid supplements in diabetic neuropathy. Investigative Ophthalmology and Visual Science 51, 1755–1764.CrossRefGoogle ScholarPubMed
Yonemura, D (1978). Electrophysiological study on activities of neuronal and non-neuronal retinal elements in man with reference to its clinical application. Japanese Journal of Ophthalmology 22, 195–213.Google Scholar
Yonemura, D., Aoki, T. & Tsuzuki, K. (1962). Electroretinogram in diabetic retinopathy. Archives of Ophthalmology 68, 19–24.CrossRefGoogle ScholarPubMed
Zheng, L., Du, Y., Miller, C., Gubitosi-Klug, R.A., Kern, T.S., Ball, S. & Berkowitz, B.A. (2007). Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes. Diabetologia 50, 1987–1996.CrossRefGoogle ScholarPubMed