Dual contribution of TRPV4 antagonism in the regulatory effect of vasoinhibins on blood-retinal barrier permeability: diabetic milieu makes a difference

David Arredondo Zamarripa,Alessandra Fiorio Pla,Ana María Bautista Cortés,Osvaldo Vázquez Ruíz,Natalia Prevarskaya,Wolfgang Liedtke,Fernando López-Casillas,Michela Bernardini,Carmen Clapp,Ramsés Noguez Imm,Stéphanie Thébault,Dimitra Gkika

doi:10.1038/s41598-017-13621-8

Abstract

Breakdown of the blood-retinal barrier (BRB), as occurs in diabetic retinopathy and other chronic retinal diseases, results in vasogenic edema and neural tissue damage, causing vision loss. Vasoinhibins are N-terminal fragments of prolactin that prevent BRB breakdown during diabetes. They modulate the expression of some transient receptor potential (TRP) family members, yet their role in regulating the TRP vanilloid subtype 4 (TRPV4) remains unknown. TRPV4 is a calcium-permeable channel involved in barrier permeability, which blockade has been shown to prevent and resolve pulmonary edema. We found TRPV4 expression in the endothelium and retinal pigment epithelium (RPE) components of the BRB, and that TRPV4-selective antagonists (RN-1734 and GSK2193874) resolve BRB breakdown in diabetic rats. Using human RPE (ARPE-19) cell monolayers and endothelial cell systems, we further observed that (i) GSK2193874 does not seem to contribute to the regulation of BRB and RPE permeability by vasoinhibins under diabetic or hyperglycemic-mimicking conditions, but that (ii) vasoinhibins can block TRPV4 to maintain BRB and endothelial permeability. Our results provide important insights into the pathogenesis of diabetic retinopathy that will further guide us toward rationally-guided new therapies: synergistic combination of selective TRPV4 blockers and vasoinhibins can be proposed to mitigate diabetes-evoked BRB breakdown.

Highlights

Breakdown of the blood-retinal barrier (BRB), as occurs in diabetic retinopathy and other chronic retinal diseases, results in vasogenic edema and neural tissue damage, causing vision loss
Projections in z showed that TRP vanilloid subtype 4 (TRPV4) localizes to the basal outer non-pigmented part of the retinal pigment epithelium (RPE), while RPE-65 is in the cytosol (Fig. 1B)
Our previous work showed that vasoinhibins have significant therapeutic potential for the control of diabetic retinopathy and macular edema since they are natural inhibitors of angiogenesis and BRB breakdown[9,10,11,12,49]

Summary

Introduction

Breakdown of the blood-retinal barrier (BRB), as occurs in diabetic retinopathy and other chronic retinal diseases, results in vasogenic edema and neural tissue damage, causing vision loss. Vasoinhibins are N-terminal fragments of prolactin that prevent BRB breakdown during diabetes They modulate the expression of some transient receptor potential (TRP) family members, yet their role in regulating the TRP vanilloid subtype 4 (TRPV4) remains unknown. We found TRPV4 expression in the endothelium and retinal pigment epithelium (RPE) components of the BRB, and that TRPV4-selective antagonists (RN-1734 and GSK2193874) resolve BRB breakdown in diabetic rats. The BRB is comprised of inner and outer components that mainly refer to vascular endothelial and retinal pigment epithelial (RPE) cells, respectively[1]. Further evidence supports the idea that vasoinhibins regulate Ca2+ homeostasis by interfering with the activity of the Ca2+-permeable transient receptor potential (TRP) family members, decreasing the expression of canonical subfamily member 5 protein (TRPC5) mRNA in endothelial cells[16]

Methods

Results

Conclusion