losartan-potassium and Macular-Degeneration

This population-based retrospective cohort study investigated the effectiveness of erythropoietin (EPO) treatment in reducing the risk of age-related macular degeneration (AMD) in hemodialysis patients, using the National Health Insurance Research Data of Taiwan. From the database, we identified 147,318 end-stage renal disease (ESRD) patients on hemodialysis who had been diagnosed in 2000−2014 to establish the propensity-score-matched EPO user cohort and non-EPO user cohort with equal sample size of 15,992. By the end of 2016, the cumulative incidence of AMD in EPO users was about 3.29% lower than that in non-EPO users (Kaplan−Meier survival p < 0.0001). The risk of AMD was 43% lower in EPO users than in non-EPO users, with an adjusted hazard ratio (aHR) of 0.57 (95% confidence interval (CI) = 0.51−0.64) estimated in the multivariate Cox model. A significant negative dose−response relationship was identified between the EPO dosage and the risk of AMD (p < 0.0001). Another beneficial effect of EPO treatment was a reduced risk of both exudative AMD (aHR = 0.48, 95% CI = 0.40−0.61) and non-exudative AMD (aHR = 0.61, 95% CI = 0.53−0.69), also in similar dose−response relationships (p < 0.0001). Our findings suggest that EPO treatment for hemodialysis patients could reduce AMD risk in a dose−response relationship.

Topics: Cohort Studies; Epoetin Alfa; Erythropoietin; Humans; Incidence; Macular Degeneration; Renal Dialysis; Retrospective Studies; Risk Factors

Hypoxia associated with the high metabolic demand of rods has been implicated in the pathology of age-related macular degeneration (AMD), the most common cause of adult blindness in the developed world. The majority of AMD-associated severe vision loss cases are due to exudative AMD, characterized by neovascularization. To further investigate the causes and histopathology of exudative AMD, we conditionally induced hypoxia in a novel preclinical AMD model (Pde6gcreERT2/+;Vhl-/-) by targeting Vhl and used multimodal imaging and immunohistochemistry to track the development of hypoxia-induced neovascularization. In addition to developing a preclinical model that phenocopies exudative AMD, our studies revealed that the photoreceptor hypoxic response initiates and drives type 3 neovascularization, mainly in the outer retina. Activation of the VHL-HIF1a-VEGF-EPO pathway in the adult retina led to long-term neovascularization, retinal hemorrhages and compromised retinal layers. Our novel preclinical model would accelerate the testing of therapies that use metabolomic approaches to ameliorate AMD.

Topics: Animals; Erythropoietin; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Macular Degeneration; Mice; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A

Age-related macular degeneration (AMD), affecting the retinal pigment epithelium (RPE), is the leading cause of blindness in middle-aged and older people in developed countries. Genetic and environmental risk factors have been identified, but no effective cure exists. Using a mouse model we show that a transmembrane prolyl 4-hydroxylase (P4H-TM), which participates in the oxygen-dependent regulation of the hypoxia-inducible factor (HIF), is a potential novel candidate gene for AMD. We show that P4h-tm had its highest expression levels in the mouse RPE and brain, heart, lung, skeletal muscle and kidney. P4h-tm

Topics: Animals; Brain; Disease Models, Animal; Erythropoietin; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Kidney; Kidney Diseases; Lung; Macular Degeneration; Mice; Muscle, Skeletal; Myocardium; Prolyl Hydroxylases; Retinal Pigment Epithelium; Tissue Distribution

The purpose of this article is to propose a novel therapeutic approach to the treatment of age-related macular degeneration (ARMD), the leading cause of blindness in the elderly population (over 60 years of age) in developed countries. Although recent advances have been made in the treatment of the neovascular form of ARMD, there is still no effective treatment for the most prevalent atrophic form of ARMD. Although the exact etiology and molecular pathogenesis of the atrophic ARMD are not fully understood, it is believed that oxidative stress and local inflammation play a major role in the pathologic processes and that the disease is triggered by dysfunction in the retinal pigment epithelia, leading to the degeneration of macular photoreceptor cells, followed by irreversible loss of vision. Considering that erythropoietin (EPO) has antioxidant, anti-inflammatory, and neuroprotective properties, we hypothesize that it can be developed as a novel therapeutic agent for the treatment of the atrophic form of ARMD. Future studies are needed to confirm or rule out this hypothesis. If successful, such studies may also help shield the lights on molecular mechanisms of atrophic ARMD.

Topics: Erythropoietin; Humans; Macular Degeneration

Oxidative damage from reactive oxygen species (ROS) has been implicated in many diseases, including age-related macular degeneration, in which the retinal pigment epithelium (RPE) is considered a primary target. The aim of this study was to determine whether erythropoietin (EPO) protects cultured human RPE cells against oxidative damage and to identify the pathways that may mediate protection. EPO (1 IU/ml) significantly increased the viability of oxidant-treated RPE cells, decreased the release of the inflammatory cytokines tumor necrosis factor-alpha and interleukin-1beta, recovered the RPE cells' barrier integrity disrupted by oxidative stress, prevented oxidant-induced cell DNA fragmentation and membrane phosphatidylserine exposure, and also reduced the levels of oxidant-induced intracellular ROS and restored cellular antioxidant potential, total antioxidant capacity, glutathione peroxidase, and superoxide dismutase and decreased malondialdehyde, the end product of lipid peroxidation. EPO inhibited caspase-3-like activity. Protection by EPO was partly dependent on the activation of Akt1 and the maintenance of the mitochondrial membrane potential. No enhanced or synergistic protection was observed during application of Z-DEVD-FMK (caspase-3 inhibitor) combined with EPO compared with cultures exposed to EPO and H(2)O(2) alone. Together, these results suggest that EPO could protect against oxidative injury-induced cell death and mitochondrial dysfunction in RPE cells through modulation of Akt1 phosphorylation, mitochondrial membrane potential, and cysteine protease activity.

Topics: Aging; Apoptosis; Caspase Inhibitors; Cells, Cultured; Cysteine Endopeptidases; Cytoprotection; DNA Damage; Erythropoietin; Humans; Interleukin-1beta; Lipid Peroxidation; Macular Degeneration; Membrane Potential, Mitochondrial; Oligopeptides; Oxidative Phosphorylation; Oxidative Stress; Proto-Oncogene Proteins c-akt; Retinal Pigment Epithelium; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Oxidative damage of the retinal pigment epithelium (RPE) may play a role in the development and progression of age-related macula degeneration (ARMD). Therapeutic reduction of oxidative stress failed or had only slight effects in ARMD patients. This study evaluates antiapoptotic properties of erythropoietin (epo) at the RPE as a novel approach to protect RPE cells against oxidative damage.. Cultured ARPE-19 cells were exposed to hydroxyl (OH) radicals generated from H(2)O(2) under catalysis of Fe(3+) (Fenton reaction) for 5 min. Apoptosis rate was determined by Annexin V labelling and terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling assay. Epo was added in concentrations from 0 to 100 U/ml to the media 24 and 1 h before radical exposure as well as shortly after radical exposure. Expression of epo receptor was determined by western blotting.. Hydroxyl radical exposure induced an increase of apoptosis rate from virtually 0 to 11.8+/-1.7%. Apoptosis was detectable up to 24 h after radical exposure and reached its maximum after 6 h. Epo reduced apoptosis rate by up to 88% even if applied after the radical exposure. Best protection was achieved at 5 U/ml epo. Western blot confirmed presence of epo receptor independent of a pre-incubation of the cells with epo.. Epo exerts antiapoptotic effects on cultured RPE cells even if applied after the radical exposure. This might qualify epo as future candidate for therapy and prevention of dry ARMD.

Topics: Apoptosis; Blotting, Western; Cells, Cultured; Erythropoietin; Humans; Hydroxyl Radical; Macular Degeneration; Oxidative Stress; Receptors, Erythropoietin; Retinal Pigment Epithelium

The purpose of this study was to evaluate whether the concentration of erythropoietin as another potent ischemia-induced angiogenic factor is elevated in eyes with neovascular (age-related macular degeneration [AMD]) or oedematous (diabetic retinopathy) maculopathies. The clinical comparative study included 28 patients with diabetic macular oedema, 59 patients with exudative AMD, and 49 patients with cataract. For all patients, aqueous humour was collected during cataract surgery or during an intravitreal injection of triamcinolone acetonide. Erythropoietin levels were measured using a solid-phase chemiluminescence immunoassay. The mean concentration of erythropoietin was significantly higher in the diabetic group (60.1 +/- 46.7 mUnits/mL; P < 0.001) than in the age-related macular degeneration group (22.9 +/- 23.2 mUnits/mL) and in the control group (22.0 +/- 21.0 mUnits/mL; P < 0.001). The two latter groups did not vary significantly (P = 0.41). The results indicate that erythropoietin may be present in considerably higher concentrations in eyes with diabetic macular oedema than in eyes with exudative AMD or normal eyes.

Topics: Aged; Aqueous Humor; Cataract; Diabetic Retinopathy; Erythropoietin; Exudates and Transudates; Humans; Luminescent Measurements; Macular Degeneration; Macular Edema

Circulating hematopoietic stem cells (HSCs) appear to have roles in the formation of choroidal neovascularization (CNV) in age-related macular degeneration (AMD). This study was conducted to investigate whether the number or function of HSCs plays a role in neovascular AMD.. Eighty-one patients with neovascular AMD who underwent comprehensive fundus examinations every 3 months were included. The number of CD34(+) HSCs isolated from peripheral blood was counted by flow cytometry. Serum cytokine levels were assessed by enzyme-linked immunosorbent assay. To examine the function of circulating HSCs, mononuclear cells were cultured and then colony forming unit (CFU-EC) and migration were measured.. The number of circulating CD34(+) HSCs was significantly increased in the patients with active CNV without major systemic diseases (stable: 3.8 +/- 0.3 cells/microL, active: 5.5 +/- 0.7 cells/microL, stable versus active: P < 0.05). The number of HSCs correlated positively with the erythropoietin serum level (r = 0.47, P = 0.002). Although there was no significant difference in the CFU-EC between the patients with CNV and the control subjects, a significant decrease of CFU-EC was observed in the patients with bilateral or larger CNV.. The findings suggest that CD34(+) HSCs may be recruited from bone marrow through a signal from active CNV. Furthermore, HSCs may play a role in the severity of CNV.

Topics: Aged; Aged, 80 and over; Angiopoietin-1; Antigens, CD34; Blood Cell Count; Cell Culture Techniques; Cell Movement; Chemokine CXCL12; Choroidal Neovascularization; Colony-Forming Units Assay; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Flow Cytometry; Hematopoietic Stem Cells; Humans; Macular Degeneration; Male; Middle Aged; Vascular Endothelial Growth Factor A