The ghrelin-GHSR-1a pathway inhibits high glucose-induced retinal angiogenesis in vitro by alleviating endoplasmic reticulum stress

Abstract

Background To investigate the effect of ghrelin, a brain-gut peptide hormone, on high glucose-induced retinal angiogenesis in vitro and explore its association with endoplasmic reticulum (ER) stress. Methods Human retinal microvascular endothelial cells (HRMECs) were first divided into control and high-glucose groups, and the mRNA and protein expression levels of the receptor for ghrelin [growth hormone secretin receptor 1a, (GHSR-1a)] in cells were determined. HRMECs were then treated with high glucose alone or in combination with ghrelin or siGHSR-1a, and cell viability, migration, tube formation and the expression of the ER stress-related proteins PERK, ATF4 and CHOP were detected. Finally, to clarify whether the effects of ghrelin are related to ER stress, tunicamycin, an inducer of ER stress, was used to treat HRMECs, and cell viability, cell migration, and tube formation were evaluated. Results GHSR-1a expression in HRMECs at both the mRNA and protein levels was inhibited by high-glucose treatment. Under high-glucose conditions, ghrelin promoted cell viability and inhibited migration and tube formation, which were blocked by siGHSR-1a treatment. Ghrelin inhibited the increases in the protein levels of p-PERK, ATF4 and CHOP induced by high-glucose treatment, and combination treatment with siGHSR-1a reversed this effect of ghrelin. When tunicamycin was added, the effects of ghrelin on cell viability, migration and tube formation were all weakened. Conclusions This study experimentally revealed that ghrelin can inhibit high glucose-induced retinal angiogenesis in vitro through GHSR-1a, and alleviation of ER stress may be one of the mechanisms underlying this effect.

Cortistatin deficiency reveals a dysfunctional brain endothelium with impaired gene pathways, exacerbated immune activation, and disrupted barrier integrity

“…ECs from peripheral murine and human vessels express the neuropeptides somatostatin, cortistatin, and ghrelin, and their corresponding receptors [ 24 , 25 ]. However, the expression of these neuropeptides and their receptors in brain ECs is either absent or poorly documented [ 24 , 26 ].…”

“…ECs from peripheral murine and human vessels express the neuropeptides somatostatin, cortistatin, and ghrelin, and their corresponding receptors [ 24 , 25 ]. However, the expression of these neuropeptides and their receptors in brain ECs is either absent or poorly documented [ 24 , 26 ]. Thus, using methodologies with different sensitivity, we first investigated the relative expression of the components related to the cortistatin–somatostatin system in b.End5 murine brain ECs.…”

“…Finally, from a therapeutic point of view, our results suggest that the beneficial role of cortistatin could be exerted on brain endothelial cells in an autocrine/paracrine manner. While protective effects of somatostatin, ghrelin, and receptors-agonists in the endothelium have been reported [ 24 , 26 , 66 ], controversial findings regarding the pro- and anti-angiogenic properties of ghrelin [ 24 , 67 ] and somatostatin-induced hyperpermeability have been observed [ 68 ]. However, similar studies have never been conducted with cortistatin.…”

Changes in Circulating Acylated Ghrelin and Neutrophil Elastase in Diabetic Retinopathy

“…Interestingly, previous preclinical studies also evidenced a protective role of ghrelin in DR in vitro and in vivo models [17,18]. Specifically, ghrelin was shown to prevent cell death and to reduce pro-inflammatory interleukins in human retinal epithelial cells (ARPE- 19) and in human retinal microvascular endothelial cells (HMRECs) exposed to high glucose [17,18]. Moreover, ghrelin was found to reduce blood glucose levels and to prevent morphological alterations in retinal layers in diabetic rats, by attenuating retinal cell apoptosis and the formation of degenerate capillaries [17].…”

“…Beyond its role as an orexigenic signal [14], ghrelin has been reported to mediate antiapoptotic, autophagic, and anti-inflammatory effects at the level of the eye structures, for example, in the epithelial cells of the lens membrane [15] and in the retina [16]. Interestingly, previous preclinical studies also evidenced a protective role of ghrelin in DR in vitro and in vivo models [17,18]. Specifically, ghrelin was shown to prevent cell death and to reduce pro-inflammatory interleukins in human retinal epithelial cells (ARPE- 19) and in human retinal microvascular endothelial cells (HMRECs) exposed to high glucose [17,18].…”