losartan-potassium and Ocular-Hypertension

This study aimed to investigate the impacts of erythropoietin (EPO) on the electroretinogram b‑wave (ERG‑b), and on the mRNA and protein expression levels of hypoxia‑inducible factor‑1α (HIF‑1α), inducible nitric oxide synthase (iNOS), cyclooxygenase‑2 (COX‑2) and caspase‑9 in chronic ocular hypertension rats. Episcleral vein cauterization (EVC) was used to establish the chronic ocular hypertension rat model based on the intraocular pressure (IOP) value. ERG‑b and mRNA and protein expression levels of HIF‑1α, iNOS, COX‑2 and caspase‑9 in normal, EVC‑treated and EVC combined with EPO (EVC+EPO)‑treated rats were measured by electroretinography, RT‑PCR and western blotting, respectively. Moreover, the correlations of HIF‑1α with IOP, ERG‑b, iNOS, COX‑2 and caspase‑9 were evaluated. The mRNA and protein expression levels of HIF‑1α, iNOS, COX‑2 and caspase‑9 in EVC‑treated rats were increased significantly compared with normal rats. The peak expression levels of HIF‑1α, iNOS, COX‑2 and caspase‑9 were respectively obtained 7, 7, 7 and 14 days postoperatively. Compared with EVC‑treated rats, EPO administration weakened the mRNA and protein expression levels of HIF‑1α, iNOS, COX‑2 and caspase‑9. The mRNA expression level of HIF‑1α demonstrated a significant positive correlation with IOP and ERG‑b. HIF‑1α was positively correlated with iNOS, COX‑2 and caspase‑9 at the mRNA and protein levels. The protective effect of EPO on the retina of chronic ocular hypertension rats may be mediated by the HIF‑1 signaling pathway involving iNOS, COX‑2 and caspase‑9.

Topics: Animals; Caspase 9; Chronic Disease; Cyclooxygenase 2; Disease Models, Animal; Electroretinography; Epoetin Alfa; Erythropoietin; Hypoxia-Inducible Factor 1, alpha Subunit; Intraocular Pressure; Male; Neuroprotective Agents; Nitric Oxide Synthase Type II; Ocular Hypertension; Rats; Rats, Wistar; Recombinant Proteins; Retina; RNA, Messenger; Signal Transduction

To determine expression, cellular distribution, and regulation of hemoglobin (Hb) in normal and glaucomatous tissues.. Proteomic analysis of Hb expression was conducted on protein samples from ocular hypertensive and control rat eyes and human donor eyes with or without glaucoma. Proteomic findings were validated by quantitative (q)RT-PCR, Western blot analysis, immunohistochemistry, and the analysis of new Hb synthesis in culture. Hypoxic regulation of Hb expression was also studied in primary cultures of rat RGCs and macroglia and after transfer of the glia-conditioned medium to RGCs. The role of erythropoietin (EPO) signaling in Hb induction and cell survival was determined by applying recombinant (r)EPO treatment and performing EPO neutralization experiments by using soluble EPO receptor treatment of hypoxic cultures.. In vivo findings revealed Hb expression in the retina and optic nerve head macroglia and RGCs, suggesting an approximately two-fold upregulation in ocular hypertensive rat eyes and glaucomatous human donor eyes relative to the control eyes. In vitro findings collectively supported that hypoxia boosts glial Hb expression through hypoxia-inducible EPO signaling in an autocrine manner. Based on passive transfer experiments, hypoxia-induced production of glial EPO was also found to upregulate Hb expression in RGCs in a paracrine manner, thereby increasing the hypoxic survival of these neurons.. Findings of this study provide new insights into tissue oxygen transport in the inner retina and optic nerve head through the regulated expression of Hb in macroglia and RGCs. Upregulation of Hb expression appears to be an intrinsic protective mechanism to facilitate cellular oxygenation and may also provide free radical scavenging.

Topics: Aged; Aged, 80 and over; alpha-Globins; Animals; beta-Globins; Biological Transport; Blotting, Western; Cell Survival; Cells, Cultured; Disease Models, Animal; Erythropoietin; Eye Proteins; Glaucoma; Hemoglobins; Humans; Immunohistochemistry; Mass Spectrometry; Ocular Hypertension; Optic Disk; Oxygen; Rats; Rats, Inbred BN; Recombinant Proteins; Retina; Retinal Ganglion Cells; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

To investigate the effect of recombinant human erythropoietin (rhEPO) on the expression of bcl-2 protein in the retina of rabbits with acute high intraocular pressure and explore the mechanism underlying the protective effect of rhEPO on the retina against ischemia-reperfusion injury.. rhEPO was injected subcutaneously in the ear of a rabbit model of acute high intraocular pressure induced by physiological saline perfusion into the anterior chamber. Bcl-2 protein expression in the retina of the rabbits was observed by immunohistochemical staining on days 1, 3, 7, and 14 after retinal ischemia-reperfusion and compared with that in normal rabbits and untreated rabbit models.. bcl-2-positive cells were observed in the retina of normal rabbits with a mean positive cell number of 10.5-/+1.2 in each high-power visual field. Compared with that in the normal control group, the number of the positive cells decreased significantly in both the model group and EPO group (P<0.05, P<0.01), but the latter group showed a significantly greater number than the former (P<0.05 at day 7 and P<0.01 at day 14).. Systemic administration of rhEPO can up-regulate the expression of bcl-2 protein in the retina of rabbits with acute high intraocular pressure, which is probably one of the mechanisms for the protective effect of rhEPO on the retina against ischemia-reperfusion injury.

Topics: Animals; Erythropoietin; Female; Humans; Male; Ocular Hypertension; Proto-Oncogene Proteins c-bcl-2; Rabbits; Random Allocation; Recombinant Proteins; Retina

To observe the effect of recombinant human erythropoietin (rhEPO) on the expression of hypoxia inducible factor-1alpha (HIF-1alpha) in the retina of rabbits with acute high intraocular pressure and investigate the mechanism of rhEPO in protecting the retina from ischemia-reperfusion injury.. Acute high intraocular pressure was induced in the rabbits by perfusion of normal saline into the anterior chamber, and rhEPO was injected subcutaneously. The changes in HIF-1alpha protein expression in the retina was observed by immunohistochemistry on days 1, 3, 7, and 14 after retinal ischemia- reperfusion.. HIF-1alpha expression was not observed in the retina of the normal control rats, but intense HIF-1alpha expression was found in the model group (P<0.01). In rabbits with rhEPO injection and those in the model group, the patterns of HIF-1alpha expression alterations were similar, but the HIF-1alpha-positive cells in the retina were significantly fewer in rhEPO group (P<0.05).. rhEPO can down-regulate HIF-1alpha expression in the retina of rabbits with acute high intraocular pressure, which may be one of the mechanisms that rhEPO protects the retina from ischemia-reperfusion injury.

Topics: Animals; Down-Regulation; Erythropoietin; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Neuroprotective Agents; Ocular Hypertension; Rabbits; Recombinant Proteins; Reperfusion Injury; Retina; Retinal Vessels

The aim of this study was to clarify whether erythropoietin (EPO) with a retrobulbar administration could protect retinal ganglion cells (RGCs) from acute elevated intraocular pressure (IOP).. The anterior chamber of the right eye was cannulated, and the IOP was raised to 70 mm Hg for a duration of up to 60 min. One thousand (1000) units of recombinant erythropoietin (rhEPO) or vehicle solution was administered a retrobulbar injection immediately after the onset of the acute elevated IOP. After 1 week, RGCs were labeled with a commercially available retrograde tracer applied to the superior colliculi. Densities of surviving RGCs were estimated by counting retrograde-tracer-labeled cells in whole-mounted retinas. The ultrastructural changes of RGCs were observed by transmission electron microscope. Immunocytochemistry was used to detect EPO and erythropoietin receptor (EPOR) expression in the RGCs layer.. The acute elevated IOP could result in the loss of RGCs. The number of surviving RGCs per square millimeter in the eyes of the acute elevated IOP + rhEPO retrobulbar injection group was significantly higher than that in the eyes of the acute elevated IOP and acute elevated IOP + vehicle solution retrobulbar injection groups (P < 0.05). The number of the organelles in the RGCs plasm decreased, but some intact mitochondrian still existed in the RGCs plasm in the eyes of the acute elevated IOP + rhEPO retrobulbar injection group. The densities of EPO and EPOR expression of the RGCs layer in the eyes of the acute elevated IOP + rhEPO retrobulbar injection group were significantly higher than that in the eyes of the acute elevated IOP and acute elevated IOP + vehicle solution retrobulbar injection groups (P < 0.01).. EPO with a retrobulbar administration could protect RGCs from acute elevated IOP.

Topics: Acute Disease; Animals; Cell Survival; Erythropoietin; Immunohistochemistry; Intraocular Pressure; Male; Microscopy, Electron, Transmission; Neuroprotective Agents; Ocular Hypertension; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin; Recombinant Proteins; Retinal Ganglion Cells

Recent studies have showed that erythropoietin (EPO) is a neuroprotectant for central nerve system neurons in addition to being a hematopoietic cytokine in response to hypoxia. In this study, we investigate the role of the EPO/EPO receptor (EPOR) system in the rat retina after ocular hypertension injury that mimics glaucoma.. Elevated intraocular pressure was induced by laser coagulation of the episcleral and limbal veins. Expression of EPO and EPOR in the normal and glaucomous retinas was investigated by immunohistochemistry and Western blot. To examine the effects of endogenous EPO on the survival of retinal ganglion cells (RGCs) subjected to hypertensive injury, soluble EPOR was directly injected into the vitreous body. Recombinant human EPO was both intravitreally and systemically administrated to study the effect of exogenous EPO on the survival of RGCs after ocular hypertension injury.. Immunohistochemistry studies identified Müller cells as the main source of EPO in the normal retina. Expression of EPO and EPOR proteins was increased significantly 2 weeks after ocular hypertension. RGCs, amacrine and bipolar cells all demonstrated an increased expression of EPOR after ocular hypertension. Neutralization of endogenous EPO with soluble EPOR exacerbated ocular hypertensive injury, suggesting a role of the EPO/EPOR system in the survival of RGCs after injury. Similarly, topical and systemic administration of recombinant human EPO rescues RGCs after chronic ocular hypertension.. These results indicate that an endogenous EPO/EPOR system participates in intrinsic recovery mechanisms after retina injury and RGCs might be rescued by exogenous administration of EPO.

Topics: Animals; Cell Survival; Chronic Disease; Erythropoietin; Female; Neuroprotective Agents; Ocular Hypertension; Optic Nerve Injuries; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin; Retinal Ganglion Cells; Solubility; Up-Regulation

To investigate the protective effect of recombinant human erythropoietin (rhEPO) on retinal ischemic injury induced by raising intraocular pressure.. Twelve New Zealand rabbits were divided into the model group (n=6) and the EPO group (n=6). Either of bilateral eyes was randomly made into the acutely high intraocular pressure model using the method of saline perfusion into anterior chamber. After the model was made, rhEPO 100 IU x kg(-1) was injected into the hypodermic tissue of EPO group rabbits twice a week for one week. Flash electroretinogram (ERG) was detected 30 min before and at 1, 3, 7, and 14 days after perfusion, respectively.. The amplitude of ERG-b wave had no significant difference in the EPO group compared with that in the model group before anterior chamber perfusion (P > 0.05). The amplitude of ERG-b wave dropped down to the lowest at 1 day after perfusion and could not come back to the baseline in the model group (P < 0.05). The resemble situation was in the EPO group except that the amplitude of ERG-b wave came back to the baseline at 14 days (P > 0.05).. EPO can improve the amplitude of ERG-b wave following retinal ischemia. This indicates that EPO has the potential to be an optimal neuroprotective agent.

Topics: Animals; Electroretinography; Erythropoietin; Female; Humans; Male; Neuroprotective Agents; Ocular Hypertension; Rabbits; Recombinant Proteins; Reperfusion Injury; Retina; Retinal Diseases