Heme oxygenase in the retina in diabetes.
BACKGROUND
Heme oxygenase (HO) isoforms, HO-1, and HO-2, are responsible for heme breakdown to iron and carbon monoxide (CO). HO may respond to oxidative stress and may modulate the expression of vasoactive factors like nitric oxide (NO). Since diabetes induced oxidative stress may change HO, the present study examined whether diabetes is associated with HO alterations, its relationship with NO, endothelin-1(ET-1) and the functional significance.


METHODS
Male SD rats with Streptozotocin induced diabetes were investigated after six-weeks. Poorly controlled diabetic animals were randomized to one of three treatment groups (n = 6 each group); a) untreated, b) HO-1 inhibitor SnPP-IX (50 micromol/kgIP/day), c) NO donor molsidomine (120 mg/L PO/day) and were compared with age and sex matched non diabetic control animals with or without SnPP-IX treatment. Color Doppler ultrasound analysis was used to determine retinal resistivity index (RI). mRNA for HO-1, HO-2, ET-1, eNOS and iNOS were analyzed with competitive RT-PCR. HO distribution in the retina was investigated by immunocytochemistry.


RESULTS
Diabetic animals expressed lower body weight, higher blood glucose and increased glycated hemoglobin levels. HO-1 and HO-2 immuno-reactivity were identified in the retina. Diabetes induced increased RI was associated with up-regulation of both ET-1 and HO-1 mRNA expression but not eNOS or iNOS mRNA. Both SnPP-IX and molsidomine treatments prevented a diabetes increase of RI, in spite of increased ET-1 expression and were associated with increased iNOS mRNA.


CONCLUSIONS
The present data suggests that the HO system is up-regulated in short term diabetes leading to HO and NO interactions which may modulate vascular function in the retina.
Cukiernik
Mark
M
Department of Pathology, University of Western Ontario, Ontario, London, Canada.
Mukherjee
Suranjana
S
Downey
Donal
D
Chakabarti
Subrata
S
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D019332:Endothelin-1 / Q000235:genetics; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006442:Glycated Hemoglobin / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D008297:Male; D008665:Metalloporphyrins / Q000627:therapeutic use; D008981:Molsidomine / Q000627:therapeutic use; D020030:Nitric Oxide Donors / Q000627:therapeutic use; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011524:Protoporphyrins / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D001786:Blood Glucose; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D006442:Glycated Hemoglobin; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D008665:Metalloporphyrins; D008981:Molsidomine; D020030:Nitric Oxide Donors; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011524:Protoporphyrins; D012333:RNA, Messenger; C032628:tin protoporphyrin IX; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; C105245:heme oxygenase-2