Abstract
ObjectiveThe role of the hydroxycarboxylic acid receptor 2 (HCA2) in the retinal damage induced by diabetes has never been explored. In this context, the present study highlights an upregulation of retinal HCA2 receptors in diabetic C57BL6J mice. Moreover, we illustrate that HCA2 receptors exert an anti-inflammatory effect on the retinal damage induced by diabetes when activated by the endogenous ligand β-hydroxybutyrate,MethodologySeven-to-10-week-old C57BL6J mice were rendered diabetic by a single intraperitoneal injection of streptozotocin (75 mg/kg of body weight) and monitored intermittently over a 10-week period extending from the initial diabetes assessment. Mice with a fasting blood glucose level higher than 250 mg/dl for 2 consecutive weeks after streptozotocin injection were treated twice a week with intraperitoneal injections of 25-50-100 mg/kg β-hydroxybutyrate.ResultsInterestingly, while the retinal endoplasmic reticulum stress markers (pPERK, pIRE1, ATF-6α) were elevated in diabetic C57BL6J mice, their levels were significantly reduced by the systemic intraperitoneal treatment with 50 mg/kg and 100 mg/kg β-hydroxybutyrate. These mice also exhibited high NLRP3 inflammasome activity and proinflammatory cytokine levels. In fact, the elevated levels of retinal NLRP3 inflammasome activation markers (NLRP3, ASC, caspase-1) and of the relative proinflammatory cytokines (IL-1β, IL-18) were significantly reduced by 50 mg/kg and 100 mg/kg β-hydroxybutyrate treatment. These doses also reduced the high apoptotic cell number exhibited by the diabetic mice in the retinal outer nuclear layer (ONL) and increased the ONL low connexin 43 expression, leading to an improvement in retinal permeability and homeostasis.ConclusionsThese data suggest that the systemic treatment of diabetic C57BL6J mice with BHB activates retinal HCA2 and inhibits local damage.
Highlights
Retinal damage is the most common complication of diabetes and is a major cause of several visual impairments leading to adult blindness [1]
Local hydroxycarboxylic acid receptor 2 (HCA2) receptor activation by beta-hydroxybutyrate reduces NLRP3 inflammasome in diabetic retinal damage significantly reduced by 50 mg/kg and 100 mg/kg β-hydroxybutyrate treatment
These doses reduced the high apoptotic cell number exhibited by the diabetic mice in the retinal outer nuclear layer (ONL) and increased the ONL low connexin 43 expression, leading to an improvement in retinal permeability and homeostasis
Summary
Retinal damage is the most common complication of diabetes and is a major cause of several visual impairments leading to adult blindness [1]. Diabetes-induced retinal damage is linked to interrelated pathways and mediators underlying a chronic low-grade inflammatory state [2, 3]. This results in the increased permeability of the blood-retinal barrier, leading to an ischemic event that drives angiogenesis into the retina. HCA2 seems to not be properly activated in the diabetic retina: Ghambir and colleagues have shown that following streptozotocin (STZ) administration, diabetic C57BL6J mice exhibited low endogenous BHB serum levels These levels were insufficient to significantly activate the HCA2 receptor and thereby protected the retina from diabetes-induced damage [5]. This led to the hypothesis of an exogenous supply of BHB in this model to achieve a proper HCA2 activation
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