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

Proc Natl Acad Sci U S A. 2017 Dec 12;114(50):13248-13253. doi: 10.1073/pnas.1718592114. Epub 2017 Nov 27.

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: GH; GHRH; GHRH-R; diabetic retinopathy; type 1 diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Anti-Inflammatory Agents / therapeutic use
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Cytokines / genetics
  • Cytokines / metabolism
  • Diabetic Retinopathy / drug therapy*
  • Diabetic Retinopathy / metabolism
  • GA-Binding Protein Transcription Factor / genetics
  • GA-Binding Protein Transcription Factor / metabolism
  • Growth Hormone-Releasing Hormone / agonists*
  • Growth Hormone-Releasing Hormone / antagonists & inhibitors
  • Humans
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Retina / drug effects
  • Retina / metabolism
  • Sermorelin / analogs & derivatives*
  • Sermorelin / pharmacology
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Anti-Inflammatory Agents
  • Cell Adhesion Molecules
  • Cytokines
  • GA-Binding Protein Transcription Factor
  • GHRH(1-29)NH2, (PhAc-Ada)(0)-Tyr(1), Arg(2), Fpa(5,6), Ala(8), Har(9), Tyr(Me)(10), His(11), Orn(12,) Abu(15), His(20), Orn(21), Nle(27), Arg(28), Har(29)-
  • N-Me-Tyr1,D-Ala2,Asn8,Arg29-NHCH3-JI-38
  • Vascular Endothelial Growth Factor A
  • Sermorelin
  • Growth Hormone-Releasing Hormone