title: C-type natriuretic peptide protects the retinal pigment epithelium against advanced glycation end product-induced barrier dysfunction.
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 (EC(50)= 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.
authors.affiliation: Department of Ophthalmology, Medical University of South Carolina, Storm Eye Institute, 167 Ashley Avenue, Charleston, SC 29425, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Dahrouj
authors.forename: Oday
authors.initials: O
authors.lastname: Alsarraf
authors.forename: Yueying
authors.initials: Y
authors.lastname: Liu
authors.forename: Craig E
authors.initials: CE
authors.lastname: Crosson
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Ablonczy
mesh_terms: D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D001813:Blood-Retinal Barrier / Q000187:drug effects*; D015153:Blotting, Western; D002460:Cell Line; D000242:Cyclic AMP / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D006801:Humans; D020097:Natriuretic Peptide, Brain / Q000494:pharmacology; D020098:Natriuretic Peptide, C-Type / Q000494:pharmacology*; D055213:Retinal Pigment Epithelium / Q000187:drug effects*; D012709:Serum Albumin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000093423:Glycated Serum Albumin
chemical_list: D017127:Glycation End Products, Advanced; D012709:Serum Albumin; D020097:Natriuretic Peptide, Brain; D020098:Natriuretic Peptide, C-Type; D009320:Atrial Natriuretic Factor; D000242:Cyclic AMP; D006152:Cyclic GMP; D000093423:Glycated Serum Albumin