Ghrelin Modulates Physiologic and Pathologic Retinal Angiogenesis through GHSR-1a

Zaniolo, Karine; Sapieha, Przemysław; Shao, Zhuo; Stahl, Andreas; Zhu, Tang; Tremblay, Sophie; Picard, Émilie; Madaan, Ankush; Blais, Martine; Lachapelle, Pierre; Mancini, Joseph; Hardy, Pierre; Smith, Lois E.H.; Ong, Huy; Chemtob, Sylvain

doi:10.1167/iovs.10-7152

Cited by 32 publications

(25 citation statements)

References 43 publications

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“…Consistent with a previous report, 16 our results revealed that ghrelin was mainly expressed in Müller cells in normal retinas. Elevated expression of ghrelin was observed in almost the entire COH retina, including the ganglion cell layer (GCL), the inner plexiform layer (IPL), and the outer plexiform layer (OPL) in COH retinas (Fig.…”

Section: Figure 2 Ghsr-1a Expression In Müller Cells and Rgcs Of Ratsupporting

confidence: 94%

“…14,15 Ghrelin is found in ocular tissues and may be generated directly in rat retinas. 16 The expression of ghrelin has been detected in the posterior epithelium of the iris, ciliary processes of rats, 17 and in retinal Müller cells. 16 Relative to ghrelin, GHSR-1a expression in ocular tissues is more extensive and has been found in the ciliary body, trabecular meshwork, retinal endothelial cells, choroid cells, and Müller cells, 16,18 suggesting that the ghrelin-GHSR-1a system plays a physiological role in the retina.…”

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confidence: 99%

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Ghrelin Attenuates Retinal Neuronal Autophagy and Apoptosis in an Experimental Rat Glaucoma Model

Zhu

Zhang

Liu

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Ghrelin, a natural ligand for the growth hormone secretagogue receptor type 1a (GHSR-1a), may protect retinal neurons against glaucomatous injury. We therefore characterized the underlying mechanism of the ghrelin/GHSR-1a-mediated neuroprotection with a rat chronic intraocular hypertension (COH) model. METHODS.The rat COH model was produced by blocking episcleral veins. A combination of immunohistochemistry, Western blot, TUNEL assay, and retrograde labeling of retinal ganglion cells (RGCs) was used.RESULTS. Elevation of intraocular pressure induced a significant increase in ghrelin and GHSR1a expression in retinal cells, including RGCs and Müller cells. Western blot confirmed that the protein levels of ghrelin exhibited a transient upregulation at week 2 after surgery (G2w), while the GHSR-1a protein levels were maintained at high levels from G2w to G4w. In COH retinas, the ratio of LC3-II/LC-I and beclin1, two autophagy-related proteins, were increased from G1w to G4w, and the cleavage product of caspase3, an apoptotic executioner, was detected from G2w to G4w. Intraperitoneal injection of ghrelin significantly increased the number of surviving RGCs; inhibited the changes of LC3-II/LC-I, beclin1, and the cleavage products of caspase3; and reduced the number of TUNEL-positive cells in COH retinas. Ghrelin treatment also reversed the decreased levels of p-Akt and p-mTOR, upregulated GHSR-1a protein levels, and attenuated glial fibrillary acidic protein levels in COH retinas.CONCLUSIONS. All these results suggest that ghrelin may provide neuroprotective effect in COH retinas through activating ghrelin/GHSR-1a system, which was mediated by inhibiting retinal autophagy, ganglion cell apoptosis, and Müller cell gliosis.

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Section: Figure 2 Ghsr-1a Expression In Müller Cells and Rgcs Of Ratsupporting

confidence: 94%

mentioning

confidence: 99%

Ghrelin Attenuates Retinal Neuronal Autophagy and Apoptosis in an Experimental Rat Glaucoma Model

Zhu

Zhang

Liu

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…40 At postnatal day 6 (P6) after exposure to hyperoxia (80% O 2 ) for 20 hours, there was an increase in the retinal mRNA expression of the proinflammatory cytokine, IL-1β (4.1-fold; P<0.001), the microglial marker, Iba-1 (2.6-fold; P<0.01), and the cytotoxic factor, Sema3A (2.1-fold; P<0.05), as well as other inflammatory mediators, such as tumor necrosis factor-α (2.1-fold; P<0.01) and intercellular adhesion molecule-1 (1.5-fold; P<0.05), compared with the normoxic retinas ( Figure 1); interestingly, the major inflammasome protein NOD-like receptor family pyrin domain containing-3 (NLRP3) was also increased in retina of P6 and P8 hyperoxia-exposed pups ( Figure IA in the online-only Data Supplement). mRNA expression of endogenous IL-1Ra did not significantly increase, and that of Caspase-1 and vascular endothelial growth factor (VEGF) also remained unchanged (Figure 1).…”

Section: Oir Triggers Early Production Of Il-1β and Other Inflammatormentioning

confidence: 99%

Microglia and Interleukin-1β in Ischemic Retinopathy Elicit Microvascular Degeneration Through Neuronal Semaphorin-3A

Rivera

Sitaras

Noueihed

et al. 2013

ATVB

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124

136

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Objective-Proinflammatory cytokines contribute to the development of retinal vasculopathies. However, the role of these factors and the mechanisms by which they elicit their effects in retina are not known. We investigated whether activated microglia during early stages of ischemic retinopathy produces excessive interleukin-1β (IL-1β), which elicits retinal microvascular degeneration not directly but rather by triggering the release of the proapoptotic/repulsive factor semaphorin-3A (Sema3A)

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“…This could be the results of the initial upregulated ghrelin (especially active ghrelin) levels under SGA treatments. Growth hormone-releasing hormone (GHRH) and growth hormone secretagogue (GHS) have been reported to upregulate GHS-R1a mRNA expression in rat pituitaries (Kineman et al, 1999), and ghrelin has been reported to activate GHS-R1a in the rat retina (Zaniolo et al, 2011). In addition, ghrelin treatment reversed the downregulated GHS-R1a mRNA and protein levels in the rat cerebral cortex on ischemia/reperfusion injury (Miao et al, 2007), and intravenous injection of ghrelin upregulated GHS-R1a mRNA at the Arc of the hypothalamus in rats (Nogueiras et al, 2004).…”

Section: Sgas Upregulate Ghs-r1a Receptor Expressions In the Hypothalmentioning

confidence: 99%

The role of ghrelin signalling in second-generation antipsychotic-induced weight gain

Zhang¹,

Deng²,

Huang³

2013

Psychoneuroendocrinology

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Based on clinical and animal studies, this review suggests a tri-phasic effect of second-generation antipsychotics (SGAs) on circulating ghrelin levels: an initial increase exerted by the acute effect of SGAs; followed by a secondary decrease possibly due to the negative feedback from the SGA-induced body weight gain or hyperphagia; and a final re-increase to reach the new equilibrium. Moreover, the results can also vary depending on individual SGAs, other hormonal states, dietary choices, and other confounding factors including medical history, co-treatments, age, gender, and ghrelin measurement techniques. Interestingly, rats treated with olanzapine, an SGA with high weight gain liabilities, are associated with increased hypothalamic ghrelin receptor (GHS-R1a) levels. In addition, expressions of downstream ghrelin signalling parameters at the hypothalamus, including neuropeptide Y (NPY)/agouti-related peptide (AgRP) and proopiomelanocortin (POMC) are also altered under SGA treatments. Thus, understanding the role of ghrelin signalling in antipsychotic drug-induced weight gain should offer potential novel pharmacological targets for tackling the obesity side-effect of SGAs and its associated metabolic syndrome. ABSTRACTBased on clinical and animal studies, this review suggests a tri-phasic effect of second-generation antipsychotics (SGAs) on circulating ghrelin levels: an initial increase exerted by the acute effect of SGAs; followed by a secondary decrease possibly due to the negative feedback from the SGAinduced body weight gain or hyperphagia; and a final re-increase to reach the new equilibrium.Moreover, the results can also vary depending on individual SGAs, other hormonal states, dietary choices, and other confounding factors including medical history, co-treatments, age, gender, and ghrelin measurement techniques. Interestingly, rats treated with olanzapine, an SGA with high weight gain liabilities, are associated with increased hypothalamic ghrelin receptor (GHS-R1a) levels. In addition, expressions of downstream ghrelin signalling parameters at the hypothalamus, including neuropeptide Y (NPY)/ agouti-related peptide (AgRP) and proopiomelanocortin (POMC) are also altered under SGA treatments. Thus, understanding the role of ghrelin signalling in antipsychotic drug-induced weight gain should offer potential novel pharmacological targets for tackling the obesity side-effect of SGAs and its associated metabolic syndrome.

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Ghrelin Modulates Physiologic and Pathologic Retinal Angiogenesis through GHSR-1a

Cited by 32 publications

References 43 publications

Ghrelin Attenuates Retinal Neuronal Autophagy and Apoptosis in an Experimental Rat Glaucoma Model

Ghrelin Attenuates Retinal Neuronal Autophagy and Apoptosis in an Experimental Rat Glaucoma Model

Microglia and Interleukin-1β in Ischemic Retinopathy Elicit Microvascular Degeneration Through Neuronal Semaphorin-3A

The role of ghrelin signalling in second-generation antipsychotic-induced weight gain

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