Skip to main content

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

  • IVY S. SAMUELS (a1) (a2), CHIEH-ALLEN LEE (a3), J. MARK PETRASH (a4), NEAL S. PEACHEY (a1) (a2) (a5) and TIMOTHY S. KERN (a1) (a3)...

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.

Corresponding author
*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:
Hide All
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, 20672071.
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, 236245.
Arden, G.B. & Constable, P.A. (2006). The electro-oculogram. Progress in Retinal and Eye Research 25, 207248.
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, 928938.
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, 133144.
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, 29162924.
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, 553624.
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, 247254.
Biro, K., Palhalmi, J., Toth, A.J., Kukorelli, T. & Juhasz, G. (1998). Bimoclomol improves early electrophysiological signs of retinopathy in diabetic rats. Neuroreport 9, 20292033.
Bresnick, G.H., Korth, K., Groo, A. & Palta, M. (1984). Electroretinographic oscillatory potentials predict progression of diabetic retinopathy. Preliminary report. Archives of Ophthalmology 102, 13071311.
Bresnick, G.H. & Palta, M. (1987). Oscillatory potential amplitudes. Relation to severity of diabetic retinopathy. Archives of Ophthalmology 105, 929933.
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, 401408.
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.
Coupland, S.G. (1987). A comparison of oscillatory potential and pattern electroretinogram measures in diabetic retinopathy. Documenta Ophthalmologica 66, 207218.
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, 977986.
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, C374383.
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, 305314.
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, 19771984.
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, 16691680.
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, 193211.
Hancock, H.A. & Kraft, T.W. (2004). Oscillatory potential analysis and ERGs of normal and diabetic rats. Investigative Ophthalmology and Visual Science 45, 10021008.
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, 3537.
Hers, H.G. (1962). [Increase of activity of glucose-6-phosphatase in intolerance to fructose]. Revue Internationale d’Hepatologie 12, 777782.
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, 58405846.
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, 27732780.
Hotta, N. (1995). New approaches for treatment in diabetes: Aldose reductase inhibitors. Biomedicine and Pharmacotherapy 49, 232243.
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, 199206.
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, 948954.
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, 981989.
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, 4551.
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, 613617.
Juen, S. & Kieselbach, G.F. (1990). Electrophysiological changes in juvenile diabetics without retinopathy. Archives of Ophthalmology 108, 372375.
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, 57335740.
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, 445449.
Linsenmeier, R.A. & Steinberg, R.H. (1982). Origin and sensitivity of the light peak in the intact cat eye. The Journal of Physiology 331, 653673.
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, 236253.
Lowitt, S., Malone, J.I., Salem, A., Kozak, W.M. & Orfalian, Z. (1993). Acetyl-L-carnitine corrects electroretinographic deficits in experimental diabetes. Diabetes 42, 11151118.
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, 887889.
MacGregor, L.C. & Matschinsky, F.M. (1986). Experimental diabetes mellitus impairs the function of the retinal pigmented epithelium. Metabolism: Clinical and Experimental 35, 2834.
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, 40464051.
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, 115124.
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, 20902095.
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, 133151.
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, 11171133.
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, 702705.
Phipps, J.A. & Feener, E.P. (2008). The kallikrein-kinin system in diabetic retinopathy: Lessons for the kidney. Kidney International 73, 11141119.
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, 45924600.
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, 31873194.
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, 391402.
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, 7191.
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, 34473453.
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, 231236.
Shirao, Y. & Kawasaki, K. (1998). Electrical responses from diabetic retina. Progress in Retinal and Eye Research 17, 5976.
Simo, R. & Hernandez, C. (2009). Advances in the medical treatment of diabetic retinopathy. Diabetes Care 32, 15561562.
Steinberg, R.H. (1985). Interactions between the retinal pigment epithelium and the neural retina. Documenta Ophthalmologica 60, 327346.
Steinberg, R.H. & Miller, S. (1973). Aspects of electrolyte transport in frog pigment epithelium. Experimental Eye Research 16, 365372.
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, 728730.
Strauss, O. (2005). The retinal pigment epithelium in visual function. Physiological Reviews 85, 845881.
Tzekov, R. & Arden, G.B. (1999). The electroretinogram in diabetic retinopathy. Survey of Ophthalmology 44, 5360.
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, 913920.
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, 5358.
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, 217228.
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, 22972305.
Witkovsky, P., Dudek, F.E. & Ripps, H. (1975). Slow PIII component of the carp electroretinogram. The Journal of General Physiology 65, 119134.
Wong, V.H., Bui, B.V. & Vingrys, A.J. (2011). Clinical and experimental links between diabetes and glaucoma. Clinical and Experimental Optometry 94, 423.
Wu, J., Marmorstein, A.D., Kofuji, P. & Peachey, N.S. (2004 a). Contribution of Kir4.1 to the mouse electroretinogram. Molecular Vision 10, 650654.
Wu, J., Peachey, N.S. & Marmorstein, A.D. (2004 b). Light-evoked responses of the mouse retinal pigment epithelium. Journal of Neurophysiology 91, 11341142.
Xu, H.Z. & Le, Y.Z. (2011). Significance of outer blood-retina barrier breakdown in diabetes and ischemia. Investigative Ophthalmology and Visual Science 52, 21602164.
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, 8392.
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, 17551764.
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, 195213.
Yonemura, D., Aoki, T. & Tsuzuki, K. (1962). Electroretinogram in diabetic retinopathy. Archives of Ophthalmology 68, 1924.
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, 19871996.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Visual Neuroscience
  • ISSN: 0952-5238
  • EISSN: 1469-8714
  • URL: /core/journals/visual-neuroscience
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Full text views

Total number of HTML views: 4
Total number of PDF views: 19 *
Loading metrics...

Abstract views

Total abstract views: 283 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 22nd March 2018. This data will be updated every 24 hours.