Metabolic memory in diabetes - from in vitro oddity to in vivo problem: role of apoptosis.
Retinal capillary cells undergo apoptosis before pathology characteristic of retinopathy can be observed, and the appearance of apoptotic capillary cell can predict the development of pathology. The purpose of this study is to investigate the effect of reversal of hyperglycemia on retinal capillary cell apoptosis, and identify the apoptosis encoding genes. Streptozotocin-diabetic rats were maintained either in poor glycemic control (PC, glycated hemoglobin, GHb >11%) or in good glycemic control (GC, GHb <6%) for 12 months, or allowed to be in PC for 6 months followed by GC for 6 additional months (PC-GC). Capillary cell apoptosis was determined in the trypsin-digested retinal microvasculature by TUNEL staining, and the genes encoding apoptosis were identified by Oligo GEArray rat apoptosis microarray that profiles 113 genes. Six months of good glycemic control that followed 6 months of poor control failed to attenuate the number of TUNEL-positive capillary cells in the retinal microvasculature. Twenty-three retinal genes, mainly from TNF ligand and receptor, caspase, Bcl-2 and death domain subfamilies that were upregulated by least a two-fold in PC rats remain upregulated after reversal of hyperglycemia. Thus, the continued activation of apoptosis plays a major role in the resistance of retinopathy to halt after re-institution of good glycemic control, and the regulation apoptosis machinery could help retard the progression of diabetic retinopathy.
Kowluru
Renu A
RA
Kresge Eye Institute, Wayne State University, 4717 St. Antoine, Detroit, MI 48201, USA. rkowluru@med.wayne.edu
Chan
Pooi-See
PS
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology*; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006442:Glycated Hemoglobin / Q000378:metabolism* / Q000494:pharmacology; D006943:Hyperglycemia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D020287:In Situ Nick-End Labeling / Q000379:methods; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D012171:Retinal Vessels / Q000473:pathology*; D018709:Statistics, Nonparametric
D048868:Adaptor Proteins, Signal Transducing; D005136:Eye Proteins; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin