Protective effects of agonists of growth hormone-releasing hormone (GHRH) in early experimental diabetic retinopathy

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Abstract

The potential therapeutic effects of agonistic analogs of growth hormone-releasing hormone (GHRH) and their mechanism of action were investigated in diabetic retinopathy (DR). Streptozotocin-induced diabetic rats (STZ-rats) were treated with 15 μg/kg GHRH agonist, MR-409, or GHRH antagonist, MIA-602. At the end of treatment, morphological and biochemical analyses assessed the effects of these compounds on retinal neurovascular injury induced by hyperglycemia. The expression levels of GHRH and its receptor (GHRH-R) measured by qPCR and Western blotting were significantly down-regulated in retinas of STZ-rats and in human diabetic retinas (postmortem) compared with their respective controls. Treatment of STZ-rats with the GHRH agonist, MR-409, prevented retinal morphological alteration induced by hyperglycemia, particularly preserving survival of retinal ganglion cells. The reverse, using the GHRH antagonist, MIA-602, resulted in worsening of retinal morphology and a significant alteration of the outer retinal layer. Explaining these results, we have found that MR-409 exerted antioxidant and anti-inflammatory effects in retinas of the treated rats, as shown by up-regulation of NRF-2-dependent gene expression and down-regulation of proinflammatory cytokines and adhesion molecules. MR-409 also significantly down-regulated the expression of vascular endothelial growth factor while increasing that of pigment epithelium-derived factor in diabetic retinas. These effects correlated with decreased vascular permeability. In summary, our findings suggest a neurovascular protective effect of GHRH analogs during the early stage of diabetic retinopathy through their antioxidant and anti-inflammatory properties.

Original languageEnglish (US)
Pages (from-to)13248-13253
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number50
DOIs
StatePublished - Dec 12 2017

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Growth Hormone-Releasing Hormone
Diabetic Retinopathy
Retina
Streptozocin
Hormone Antagonists
Hyperglycemia
Anti-Inflammatory Agents
Antioxidants
Retinal Ganglion Cells
Gene Expression Regulation
Capillary Permeability
Therapeutic Uses
Vascular Endothelial Growth Factor A
Up-Regulation
Down-Regulation
Western Blotting
Cytokines
N-Me-Tyr1,D-Ala2,Asn8,Arg29-NHCH3-JI-38
Wounds and Injuries

Keywords

  • Diabetic retinopathy
  • GH
  • GHRH
  • GHRH-R
  • Type 1 diabetes

ASJC Scopus subject areas

  • General

Cite this

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title = "Protective effects of agonists of growth hormone-releasing hormone (GHRH) in early experimental diabetic retinopathy",
abstract = "The potential therapeutic effects of agonistic analogs of growth hormone-releasing hormone (GHRH) and their mechanism of action were investigated in diabetic retinopathy (DR). Streptozotocin-induced diabetic rats (STZ-rats) were treated with 15 μg/kg GHRH agonist, MR-409, or GHRH antagonist, MIA-602. At the end of treatment, morphological and biochemical analyses assessed the effects of these compounds on retinal neurovascular injury induced by hyperglycemia. The expression levels of GHRH and its receptor (GHRH-R) measured by qPCR and Western blotting were significantly down-regulated in retinas of STZ-rats and in human diabetic retinas (postmortem) compared with their respective controls. Treatment of STZ-rats with the GHRH agonist, MR-409, prevented retinal morphological alteration induced by hyperglycemia, particularly preserving survival of retinal ganglion cells. The reverse, using the GHRH antagonist, MIA-602, resulted in worsening of retinal morphology and a significant alteration of the outer retinal layer. Explaining these results, we have found that MR-409 exerted antioxidant and anti-inflammatory effects in retinas of the treated rats, as shown by up-regulation of NRF-2-dependent gene expression and down-regulation of proinflammatory cytokines and adhesion molecules. MR-409 also significantly down-regulated the expression of vascular endothelial growth factor while increasing that of pigment epithelium-derived factor in diabetic retinas. These effects correlated with decreased vascular permeability. In summary, our findings suggest a neurovascular protective effect of GHRH analogs during the early stage of diabetic retinopathy through their antioxidant and anti-inflammatory properties.",
keywords = "Diabetic retinopathy, GH, GHRH, GHRH-R, Type 1 diabetes",
author = "Thounaojam, {Menaka C.} and Powell, {Folami L.} and Sagar Patel and Gutsaeva, {Diana R.} and Amany Tawfik and Smith, {Sylvia B.} and Julian Nussbaum and Block, {Norman L.} and Martin, {Pamela M.} and Schally, {Andrew V.} and Manuela Bartoli",
year = "2017",
month = "12",
day = "12",
doi = "10.1073/pnas.1718592114",
language = "English (US)",
volume = "114",
pages = "13248--13253",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
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TY - JOUR

T1 - Protective effects of agonists of growth hormone-releasing hormone (GHRH) in early experimental diabetic retinopathy

AU - Thounaojam, Menaka C.

AU - Powell, Folami L.

AU - Patel, Sagar

AU - Gutsaeva, Diana R.

AU - Tawfik, Amany

AU - Smith, Sylvia B.

AU - Nussbaum, Julian

AU - Block, Norman L.

AU - Martin, Pamela M.

AU - Schally, Andrew V.

AU - Bartoli, Manuela

PY - 2017/12/12

Y1 - 2017/12/12

N2 - The potential therapeutic effects of agonistic analogs of growth hormone-releasing hormone (GHRH) and their mechanism of action were investigated in diabetic retinopathy (DR). Streptozotocin-induced diabetic rats (STZ-rats) were treated with 15 μg/kg GHRH agonist, MR-409, or GHRH antagonist, MIA-602. At the end of treatment, morphological and biochemical analyses assessed the effects of these compounds on retinal neurovascular injury induced by hyperglycemia. The expression levels of GHRH and its receptor (GHRH-R) measured by qPCR and Western blotting were significantly down-regulated in retinas of STZ-rats and in human diabetic retinas (postmortem) compared with their respective controls. Treatment of STZ-rats with the GHRH agonist, MR-409, prevented retinal morphological alteration induced by hyperglycemia, particularly preserving survival of retinal ganglion cells. The reverse, using the GHRH antagonist, MIA-602, resulted in worsening of retinal morphology and a significant alteration of the outer retinal layer. Explaining these results, we have found that MR-409 exerted antioxidant and anti-inflammatory effects in retinas of the treated rats, as shown by up-regulation of NRF-2-dependent gene expression and down-regulation of proinflammatory cytokines and adhesion molecules. MR-409 also significantly down-regulated the expression of vascular endothelial growth factor while increasing that of pigment epithelium-derived factor in diabetic retinas. These effects correlated with decreased vascular permeability. In summary, our findings suggest a neurovascular protective effect of GHRH analogs during the early stage of diabetic retinopathy through their antioxidant and anti-inflammatory properties.

AB - The potential therapeutic effects of agonistic analogs of growth hormone-releasing hormone (GHRH) and their mechanism of action were investigated in diabetic retinopathy (DR). Streptozotocin-induced diabetic rats (STZ-rats) were treated with 15 μg/kg GHRH agonist, MR-409, or GHRH antagonist, MIA-602. At the end of treatment, morphological and biochemical analyses assessed the effects of these compounds on retinal neurovascular injury induced by hyperglycemia. The expression levels of GHRH and its receptor (GHRH-R) measured by qPCR and Western blotting were significantly down-regulated in retinas of STZ-rats and in human diabetic retinas (postmortem) compared with their respective controls. Treatment of STZ-rats with the GHRH agonist, MR-409, prevented retinal morphological alteration induced by hyperglycemia, particularly preserving survival of retinal ganglion cells. The reverse, using the GHRH antagonist, MIA-602, resulted in worsening of retinal morphology and a significant alteration of the outer retinal layer. Explaining these results, we have found that MR-409 exerted antioxidant and anti-inflammatory effects in retinas of the treated rats, as shown by up-regulation of NRF-2-dependent gene expression and down-regulation of proinflammatory cytokines and adhesion molecules. MR-409 also significantly down-regulated the expression of vascular endothelial growth factor while increasing that of pigment epithelium-derived factor in diabetic retinas. These effects correlated with decreased vascular permeability. In summary, our findings suggest a neurovascular protective effect of GHRH analogs during the early stage of diabetic retinopathy through their antioxidant and anti-inflammatory properties.

KW - Diabetic retinopathy

KW - GH

KW - GHRH

KW - GHRH-R

KW - Type 1 diabetes

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U2 - 10.1073/pnas.1718592114

DO - 10.1073/pnas.1718592114

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AN - SCOPUS:85038562492

VL - 114

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JO - Proceedings of the National Academy of Sciences of the United States of America

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