Metabolic memory phenomenon and accumulation of peroxynitrite in retinal capillaries.
OBJECTIVE
Diabetic retinopathy resists reversal after good glycemic control (GC) is reinitiated, and preexisting damage at the time of intervention is considered as the major factor in determining the outcome of the GC. This study is to investigate the role of peroxynitrite accumulation in the retinal capillaries in the failure of retinopathy to reverse after reestablishment of GC, and to determine the effect of this reversal on the activity of the enzyme responsible for scavenging mitochondrial superoxide, MnSOD.


METHODS
In streptozotocin-diabetic rats, 6 months of poor glycemic control (PC, glycated hemoglobin, GHb > 12.0%) was followed by 6 additional months of GC (GHb about 6%). The trypsin-digested retinal microvessels were prepared for immunostaining of nitrotyrosine (a measure of peroxynitrite) and for counting the number of acellular capillaries (a measure of histopathology). The retina from the other eye was used to quantify nitrotyrosine concentration, MnSOD activity and the total antioxidant capacity.


RESULTS
Reversal of hyperglycemia after 6 months of PC had no significant effect on nitrotyrosine concentration in the retina, on the nitrotyrosine-positive retinal capillary cells and on the number of acellular capillaries; the values were similar in PC-GC and PC groups. In the same rats retinal MnSOD activity remained inhibited and the total antioxidant capacity was subnormal 6 months after cessation of PC.


CONCLUSIONS
Peroxynitrite accumulation in the retinal microvasculature, the site of histopathology, fails to normalize after reversal of hyperglycemia, and superoxide remains inadequately scavenged. This failure of reversal of peroxynitrite accumulation could be, in part, responsible for the resistance of diabetic retinopathy to reverse after termination of PC.
Kowluru
Renu A
RA
Kresge Eye Institute, Wayne State University, Detroit, MI 48201, USA. rkowluru@med.wayne.edu
Kanwar
Mamta
M
Kennedy
Alexander
A
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002196:Capillaries / Q000378:metabolism / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D006442:Glycated Hemoglobin / Q000378:metabolism; D007158:Immunologic Techniques; D007328:Insulin / Q000494:pharmacology; D008297:Male; D009994:Osmolar Concentration; D030421:Peroxynitrous Acid / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D012160:Retina / Q000378:metabolism / Q000473:pathology; D012171:Retinal Vessels / Q000378:metabolism* / Q000473:pathology; D013194:Staining and Labeling; D013482:Superoxide Dismutase / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000975:Antioxidants; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007328:Insulin; D030421:Peroxynitrous Acid; D013482:Superoxide Dismutase; D014443:Tyrosine; C002744:3-nitrotyrosine