June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Natriuretic peptides regulate MAP kinases via PKG to protect the RPE from VEGF action
Author Affiliations & Notes
  • Zsolt Ablonczy
    Ophthalmology, Medical University of South Carolina, Charleston, SC
  • Mohammad Dahrouj
    Ophthalmology, Medical University of South Carolina, Charleston, SC
  • Yueying Liu
    Ophthalmology, Medical University of South Carolina, Charleston, SC
  • Kumar Sambamurti
    Ophthalmology, Medical University of South Carolina, Charleston, SC
  • Craig Crosson
    Ophthalmology, Medical University of South Carolina, Charleston, SC
  • Footnotes
    Commercial Relationships Zsolt Ablonczy, None; Mohammad Dahrouj, None; Yueying Liu, None; Kumar Sambamurti, None; Craig Crosson, Alimera Sciences (C), Lexicon Pharmaceuticals, Inc (R)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 3151. doi:
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      Zsolt Ablonczy, Mohammad Dahrouj, Yueying Liu, Kumar Sambamurti, Craig Crosson; Natriuretic peptides regulate MAP kinases via PKG to protect the RPE from VEGF action. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3151.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Diabetic retinopathy-associated vision loss is often attributed to edema within the layers of the retina. Diabetes is known to alter the levels of natriuretic peptides (NP) expressed by the retinal pigment epithelium (RPE). However, the function of these peptides and their contribution to diabetic retinopathy remains unclear. We have previously shown that NP receptor 2 (NPR-2) activation can block the breakdown of the RPE barrier. In this project, we have investigated the molecular mechanism of NP activity in the RPE.

Methods: Barrier breakdown was induced in fetal human RPE cells by 100 mg/L glycated albumin (glyc-alb) or VEGF (10 μg/L) and measured by transepithelial resistance (TER). NPs (ANP or CNP; nmol/L) were administered apically. Administration of the cGMP analog, 8-Br-cGMP (100 μmol/L), or the PKG inhibitor, KT5823 (5 μmol/L) was used to measure the involvement of signaling events downstream of NPR-2. Enzyme-linked immunoassays determined changes in VEGF secretion. VEGF-R2 was inhibited by ZM323881 (10 nmol/L). Map kinase activation was assessed by pretreatment with pathway inhibitors (U0126 for ERK1/2, SB203580 for p38, SP600125 for JNK, LY294002 for PI3K; all at 0.1-10 μM) and western blot analysis of ERK1/2.

Results: Glycated albumin induced an apically-directed VEGF release paralleled with a rapid breakdown of RPE barrier function. The glyc-alb response was reversed by the administration of ANP or CNP in a concentration-dependent fashion and also by the VEGF-R2 antagonist, ZM323881. However, VEGF-release was not significantly altered by NPs. Pretreatment with 8-Br-cGMP substituted NP-induced responses and pretreatment with KT5823 abolished any NP-responses. VEGF-induced barrier breakdown required the activity of the ERK1/2 pathway but not that of the JNK, p38 and PI3K pathways. Similarly to U0126, NPs inhibited the VEGF-induced activation of ERK1/2.

Conclusions: These studies provided evidence that in RPE cells, NPs can oppose the effects of advanced glycation end-products, one of the most important complicating factors in diabetes. NPR-2 activation induced PKG, eventually targeting the ERK1/2 MAP kinase downstream of VEGF-R2. These results are consistent with the idea that NPs are part of an endogenous system necessary for maintaining the barrier integrity of the RPE. Therefore, we conclude that NPs play a critical role in protecting vision against diabetic retinopathy and retinal edema.

Keywords: 499 diabetic retinopathy • 505 edema • 701 retinal pigment epithelium  
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