Novel role for the delta-opioid receptor in hypoxic preconditioning in rat retinas.
Delta-opioid receptor (DOR) is an oxygen-sensitive protein whose function in the rat retina is unknown. We examined whether DOR is involved in hypoxic preconditioning (HPC)-mediated retinoprotection following intraocular pressure (IOP) elevation. Rats were exposed to intermittent hypoxia (10% oxygen) to induce HPC. Unilateral retinal ischemia/reperfusion injury was induced by elevating IOP to 100 mmHg for 1 h. HPC attenuated the loss of neuronal marker expression and increased pro-apoptotic caspase 3 activity in the IOP retina. Excess superoxide production and 8-iso-prostaglandin F2alpha accumulation caused by enhanced oxidant protein expression and reduced antioxidant enzyme level after IOP elevation were largely abrogated by HPC. HPC markedly increased the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and DOR, but intravitreal administration of HIF-1alpha-specific small interfering RNA abrogated the up-regulation of DOR. This suggested that DOR functions downstream of HIF-1alpha. However, the endogenous content of leucine enkephalin in retinas was not affected by HPC or IOP. Treatment of retinas with the DOR antagonist naltrindole attenuated the HPC-induced protection and activation of extracellular signal-regulated kinase. These results suggest a novel mechanism of HPC-mediated retinoprotection whereby HIF-1alpha induces the expression of DOR, and DOR-mediated activation of extracellular signal-regulated kinase triggers cellular events that correct the redox imbalance in the post-ischemic retina.
Peng
Pai-Huei
PH
Department of Ophthalmology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
Huang
Ho-Shiang
HS
Lee
Yih-Jing
YJ
Chen
Yih-Sharng
YS
Ma
Ming-Chieh
MC
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015153:Blotting, Western; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D004743:Enkephalin, Leucine / Q000378:metabolism; D000860:Hypoxia / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D007150:Immunohistochemistry; D007429:Intraocular Pressure / Q000502:physiology; D019194:Ischemic Preconditioning; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000502:physiology*; D012160:Retina / Q000502:physiology*; D012171:Retinal Vessels / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013050:Spectrometry, Fluorescence; D013481:Superoxides / Q000378:metabolism
D000975:Antioxidants; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009292:Narcotic Antagonists; D034741:RNA, Small Interfering; D017465:Receptors, Opioid, delta; D013481:Superoxides; C075750:8-epi-prostaglandin F2alpha; D004743:Enkephalin, Leucine; D009271:Naltrexone; D015237:Dinoprost; C055382:naltrindole