Diabetes-induced impairment in visual function in mice: contributions of p38 MAPK, rage, leukocytes, and aldose reductase.
OBJECTIVE
Visual function is impaired in diabetes, but molecular causes of this dysfunction are not clear. We assessed effects of diabetes on visual psychophysics in mice, and tested the effect of therapeutic approaches reported previously to inhibit vascular lesions of the retinopathy.


METHODS
We used the optokinetic test to assess contrast sensitivity and spatial frequency threshold in diabetic C57Bl/6J mice and age-matched nondiabetic controls between 2 and 10 months of diabetes. Contributions of p38 MAP kinase (MAPK), receptor for advanced glycation end products (RAGE), leukocytes, and aldose reductase (AR) to the defect in contrast sensitivity were investigated. Cataract, a potential contributor to reductions in vision, was scored.


RESULTS
Diabetes of 2 months' duration impaired contrast sensitivity and spatial frequency threshold in mice. The defect in contrast sensitivity persisted for at least 10 months, and cataract did not account for this impairment. Diabetic mice deficient in AR were protected significantly from development of the diabetes-induced defects in contrast sensitivity and spatial frequency threshold. In contrast, pharmacologic inhibition of p38 MAPK or RAGE, or deletion of inducible nitrous oxide synthase (iNOS) from bone marrow-derived cells did not protect the visual function in diabetes.


CONCLUSIONS
Diabetes reduces spatial frequency threshold and contrast sensitivity in mice, and the mechanism leading to development of these defects involves AR. The mechanism by which AR contributes to the diabetes-induced defect in visual function can be probed by identifying which molecular abnormalities are corrected by AR deletion, but not other therapies that do not correct the defect in visual function.
Case Western Reserve University, Cleveland, Ohio, United States.
Chieh Allen
CA
Lee
Guangyuan
G
Li
Mansi D
MD
Patel
J Mark
JM
Petrash
Beth Ann
BA
Benetz
Alex
A
Veenstra
Jaume
J
Amengual
Johannes
J
von Lintig
Christopher J
CJ
Burant
Johnny
J
Tang
Timothy S
TS
Kern
D000449:Aldehyde Reductase / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D015350:Contrast Sensitivity / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003930:Diabetic Retinopathy / Q000503:physiopathology*; D004195:Disease Models, Animal; D007962:Leukocytes / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011601:Psychophysics; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology; D012684:Sensory Thresholds / Q000502:physiology; D013028:Space Perception / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D000449:Aldehyde Reductase; D048051:p38 Mitogen-Activated Protein Kinases
contrast senstivity; diabetic retinopathy; spatial frequency threshold