RESUMEN
Diabetic retinopathy remains a major cause of vision loss worldwide. Mineralocorticoid receptor (MR) pathway activation contributes to diabetic nephropathy, but its role in retinopathy is unknown. In this study, we show that MR is overexpressed in the retina of type 2 diabetic Goto-Kakizaki (GK) rats and humans and that cortisol is the MR ligand in human eyes. Lipocalin 2 and galectin 3, two biomarkers of diabetes complications regulated by MR, are increased in GK and human retina. The sustained intraocular delivery of spironolactone, a steroidal mineralocorticoid antagonist, decreased the early and late pathogenic features of retinopathy in GK rats, such as retinal inflammation, vascular leakage, and retinal edema, through the upregulation of genes encoding proteins known to intervene in vascular permeability such as Hey1, Vldlr, Pten, Slc7a1, Tjp1, Dlg1, and Sesn2 but did not decrease VEGF. Spironolactone also normalized the distribution of ion and water channels in macroglial cells. These results indicate that MR is activated in GK and human diabetic retina and that local MR antagonism could be a novel therapeutic option for diabetic retinopathy.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Retinopatía Diabética/etiología , Receptores de Mineralocorticoides/metabolismo , Retina/patología , Neuronas Retinianas/patología , Espironolactona/farmacología , Animales , Preparaciones de Acción Retardada , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Hidrocortisona/metabolismo , Masculino , Antagonistas de Receptores de Mineralocorticoides/administración & dosificación , Antagonistas de Receptores de Mineralocorticoides/química , Antagonistas de Receptores de Mineralocorticoides/farmacología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Ratas , Ratas Endogámicas , Receptores de Mineralocorticoides/genética , Neuronas Retinianas/efectos de los fármacos , Espironolactona/administración & dosificación , Espironolactona/química , Regulación hacia Arriba , Cuerpo VítreoRESUMEN
The intravitreous injection of therapeutic proteins that neutralize vascular endothelial growth factor (VEGF) family members is efficient to reduce macular edema associated with wet age-related macular degeneration (AMD), retinal vein occlusion (RVO) and diabetic retinopathy (DR). It has revolutionized the visual prognosis of patients with macular edema. The antiedematous effect is dependent on an intravitreous dose of drug, which varies between patients and requires frequent and repeated injections to maintain its effects. At the time when optimizing the duration of anti-VEGF effects is a major challenge, understanding how anti-VEGF reduces macular edema is crucial. We discuss herein how anti-VEGF exerts antiedematous effects and raise the hypothesis that mechanisms, unrelated to VEGF neutralization, might have been underestimated.