Abstract
In diabetic retinopathy, vision loss is usually secondary to macular edema, which is thought to depend on the functional integrity of the blood-retina barrier. The levels of advanced glycation end products in the vitreous correlate with the progression of diabetic retinopathy. Natriuretic peptides (NP) are expressed in the eye and their receptors are present in the retinal pigment epithelium (RPE). Here, we investigated the effect of glycated-albumin (Glyc-alb), an advanced glycation end product model, on RPE-barrier function and the ability of NP to suppress this response. Transepithelial electrical resistance (TEER) measurements were used to assess the barrier function of ARPE-19 and human fetal RPE (hfRPE) monolayers. The monolayers were treated with 0.1–100 μg/ml Glyc-alb in the absence or presence of 1 pM to 100 nM apical atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), or C-type natriuretic peptide (CNP). Glyc-alb induced a significant reduction in TEER within 2 hours. This response was concentration-dependent (EC50= 2.3 μg/ml) with a maximal reduction of 40 ± 2% for ARPE-19 and 27 ± 7% for hfRPE at 100 μg/ml 6 hours post-treatment. One hour pretreatment with ANP, BNP, or CNP blocked the reduction in TEER induced by Glyc-alb (100 μg/ml). The suppression of the Glyc-alb response by NP was dependent on the generation of cyclic guanosine monophosphate and exhibited a rank order of agonist potency consistent with the activation of natriuretic-peptide-receptor-2 (NPR2) subtype (CNP >> BNP ≥ ANP). Our data demonstrate that Glyc-alb is effective in reducing RPE-barrier function, and this response is suppressed by NP. Moreover, these studies support the idea that NPR2 agonists can be potential candidates for treating retinal edema in diabetic patients.
Footnotes
This work was supported by in part by the National Institutes of Health National Eye Institute [Grants EY009741 (to C.E.C.) and EY019065 (to Z.A.)], the Ola B. Williams Foundation, and an unrestricted grant to Medical University of South Carolina, Storm Eye Institute, from Research to Prevent Blindness, New York, New York.
Portions of this work were presented as an abstract at the 2011 Annual Meeting of the Association for Research in Vision and Ophthalmology, Fort Lauderdale, Florida, as Dahrouj M, Ablonczy Z, and Crosson CE. Natriuretic peptides protect the RPE from AGE-induced barrier breakdown. Invest Ophthalmol Vis Sci 2011; 52:E-Abstract PN 5659.
- Received August 14, 2012.
- Accepted October 18, 2012.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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