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

Menaka C. Thounaojam, Folami L. Powell, Sagar Patel, Diana R. Gutsaeva, Amany Tawfik, Sylvia B. Smith, Julian Nussbaum, Norman L. Block, Pamela M. Martin, Andrew V. Schally, Manuela Bartoli

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • General

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