Inhibition of caspase-1/interleukin-1beta signaling prevents degeneration of retinal capillaries in diabetes and galactosemia.
The proinflammatory cytokine, interleukin (IL)-1beta, is known to induce vascular dysfunction and cell death. We investigated the role of IL-1beta and caspase-1 (the enzyme that produces it) in diabetes-induced degeneration of retinal capillaries. Caspase-1 activity is increased in retinas of diabetic and galactosemic mice and diabetic patients. First, we investigated the effect of agents known to inhibit caspase-1 (minocycline and tetracycline) on IL-1beta production and retinal capillary degeneration in diabetic and galactose-fed mice. Second, we examined the effect of genetic deletion of the IL-1beta receptor on diabetes-induced caspase activities and retinal capillary degeneration. Diabetic and galactose-fed mice were injected intraperitoneally with minocycline or tetracycline (5 mg/kg). At 2 months of diabetes, minocycline inhibited hyperglycemia-induced caspase-1 activity and IL-1beta production in the retina. Long-term administration of minocycline prevented retinal capillary degeneration in diabetic (6 months) and galactose-fed (13 months) mice. Tetracycline inhibited hyperglycemia-induced caspase-1 activity in vitro but not in vivo. Mice deficient in the IL-1beta receptor were protected from diabetes-induced caspase activation and retinal pathology at 7 months of diabetes. These results indicate that the caspase-1/IL-1beta signaling pathway plays an important role in diabetes-induced retinal pathology, and its inhibition might represent a new strategy to inhibit capillary degeneration in diabetic retinopathy.
Vincent
Jason A
JA
Case Western Reserve University, Department of Medicine, Division of Clinical and Molecular Endocrinology, Center for Diabetes Research, Cleveland, OH 44106, USA.
Mohr
Susanne
S
D000818:Animals; D002196:Capillaries / Q000503:physiopathology*; D020170:Caspase 1 / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003930:Diabetic Retinopathy / Q000517:prevention & control*; D005690:Galactose / Q000633:toxicity; D005693:Galactosemias / Q000150:complications / Q000517:prevention & control*; D005947:Glucose / Q000494:pharmacology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008911:Minocycline / Q000627:therapeutic use*; D023421:Models, Animal; D012162:Retinal Degeneration / Q000517:prevention & control*; D012171:Retinal Vessels / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013752:Tetracycline / Q000627:therapeutic use*
D061945:Caspase Inhibitors; D053583:Interleukin-1beta; D053148:Caspase 3; D020170:Caspase 1; D013752:Tetracycline; D008911:Minocycline; D005947:Glucose; D005690:Galactose