Caspase activation in retinas of diabetic and galactosemic mice and diabetic patients.
Apoptosis of retinal capillary cells begins early in diabetes and likely contributes to the capillary obliteration that is an important feature of diabetic retinopathy. Caspases are proteolytic enzymes that are closely involved in the induction and execution phases of apoptosis, but their role in the development of diabetic retinopathy has not been studied previously. Our study focused on the measurement of activities of multiple caspases in retinas of mice at different durations of diabetes. Several caspases (including caspases-1, -2, -6, -8, and -9) were activated as early as 2 months of diabetes. The caspases activity pattern changed with increasing duration of disease, suggesting a slowly developing caspases cascade. Activities of executioner caspases (e.g., cas-6 and -3) became elevated after longer duration of diabetes, and the induction of cas-3 activity was associated with the duration of diabetes at which capillary cells begin to show evidence of undergoing apoptosis. Retinas from patients with type 2 diabetes likewise showed a significant increase in activities of cas-1, -3, -4, and -6. For comparison, retinal caspases were also measured in experimental galactosemia, another model that develops a diabetic-like retinopathy. The pattern of caspases activation differed between diabetes and galactosemia, but cas-1 activity became elevated soon after elevation of blood hexose concentration in both. Caspases offer new therapeutic targets to test the role of apoptosis in the development of diabetic retinopathy.
Mohr
Susanne
S
Department of Medicine, Case Western Reserve University, Center for Diabetes Research, Cleveland, Ohio 44106, USA. sxm38@po.cwru.edu
Xi
Xia
X
Tang
Jie
J
Kern
Timothy S
TS
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D020170:Caspase 1 / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000201:enzymology* / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology; D004730:Endothelium, Vascular / Q000201:enzymology; D004789:Enzyme Activation; D005693:Galactosemias / Q000201:enzymology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012016:Reference Values; D012160:Retina / Q000201:enzymology*; D012171:Retinal Vessels / Q000503:physiopathology
D000590:Amino Acid Chloromethyl Ketones; D015415:Biomarkers; D015853:Cysteine Proteinase Inhibitors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D020170:Caspase 1