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

  1. Manuela Bartolia,2
  1. aDepartment of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912;
  2. bDepartment of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912;
  3. cDepartment of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA 30912;
  4. dDepartment of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912;
  5. eDepartment of Pathology, School of Medicine, University of Miami, Miami, FL 33136;
  6. fVeterans Affairs Medical Center, Miami, FL 33125;
  7. gSouth Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125;
  8. hDepartment of Medicine, Division of Hematology/Oncology, University of Miami, Miami, FL 33136;
  9. iDepartment of Medicine, Division of Endocrinology, University of Miami, Miami, FL 33136
  1. Contributed by Andrew V. Schally, November 1, 2017 (sent for review March 29, 2017; reviewed by Maria B. Grant, Renu Kowluru, Gianluca Tosini, and Wenbo Zhang)

Significance

The studies described here are relevant to the cure of diabetic retinopathy, a leading cause of blindness with currently limited therapeutic options. Here we provided evidence showing that agonists of growth hormone-releasing hormone (GHRH) can significantly diminish retinal neurovascular injury characterizing the early stages of diabetic retinopathy through antioxidant and anti-inflammatory effects. The results of the presented studies provide information on the potential therapeutic effects of GHRH agonists and shed light on the role of hypothalamic hormones in retinal physiology and their effect on visual disorders. In addition, our findings suggest protective effects of GHRH analogs in other disease conditions affecting retinal neuronal cells and, possibly, other nonretinal neurons.

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.

Footnotes

  • ?1Present address: Department of Ophthalmology at University of Texas Southwestern Medical Center, Dallas, TX 75219.

  • ?2To whom correspondence may be addressed. Email: andrew.schally{at}va.gov or mbartoli{at}augusta.edu.
  • Author contributions: A.V.S. and M.B. designed research; M.C.T., F.L.P., S.P., D.R.G., A.T., and M.B. performed research; S.B.S., N.L.B., A.V.S., and M.B. contributed new reagents/analytic tools; J.N. and M.B. analyzed data; S.B.S. and P.M.M. provided technical support; J.N. provided clinical input to support the study; and N.L.B., P.M.M., A.V.S., and M.B. wrote the paper.

  • Reviewers: M.B.G., University of Alabama at Birmingham; R.K., Wayne State University Kresge Eye Institute; G.T., Morehouse School of Medicine; and W.Z., University of Texas Medical Branch.

  • Conflict of interest statement: N.L.B. owns equity in Biscayne Pharmaceuticals. A.V.S. is a coinventor on the patent for GHRH agonist, assigned to the University of Miami and the Veterans Affairs Medical Center, Miami, FL. However, the investigation of the effects of GHRH agonist MR-409 was an academic endeavor without any commercial interests. The other authors declare no conflict of interest.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1718592114/-/DCSupplemental.

Online Impact