Vasoinhibins regulate the inner and outer blood-retinal barrier and limit retinal oxidative stress

David Arredondo Zamarripa, Nundehui Díaz-Lezama, Rodrigo Meléndez García, Jesús Chávez Balderas, Norma Adán, Maria G Ledesma-Colunga, Edith Arnold, Carmen Clapp, Stéphanie Thebault, David Arredondo Zamarripa, Nundehui Díaz-Lezama, Rodrigo Meléndez García, Jesús Chávez Balderas, Norma Adán, Maria G Ledesma-Colunga, Edith Arnold, Carmen Clapp, Stéphanie Thebault

Abstract

Vasoinhibins are prolactin fragments present in the retina, where they have been shown to prevent the hypervasopermeability associated with diabetes. Enhanced bradykinin (BK) production contributes to the increased transport through the blood-retina barrier (BRB) in diabetes. Here, we studied if vasoinhibins regulate BRB permeability by targeting the vascular endothelium and retinal pigment epithelium (RPE) components of this barrier. Intravitreal injection of BK in male rats increased BRB permeability. Vasoinhibins prevented this effect, as did the B2 receptor antagonist Hoe-140. BK induced a transient decrease in mouse retinal and brain capillary endothelial monolayer resistance that was blocked by vasoinhibins. Both vasoinhibins and the nitric oxide (NO) synthase inhibitor L-NAME, but not the antioxidant N-acetyl cysteine (NAC), blocked the transient decrease in bovine umbilical vein endothelial cell (BUVEC) monolayer resistance induced by BK; this block was reversed by the NO donor DETANONOate. Vasoinhibins also prevented the BK-induced actin cytoskeleton redistribution, as did L-NAME. BK transiently decreased human RPE (ARPE-19) cell monolayer resistance, and this effect was blocked by vasoinhibins, L-NAME, and NAC. DETANONOate reverted the blocking effect of vasoinhibins. Similar to BK, the radical initiator Luperox induced a reduction in ARPE-19 cell monolayer resistance, which was prevented by vasoinhibins. These effects on RPE resistance coincided with actin cytoskeleton redistribution. Intravitreal injection of vasoinhibins reduced the levels of reactive oxygen species (ROS) in retinas of streptozotocin-induced diabetic rats, particularly in the RPE and capillary-containing layers. Thus, vasoinhibins reduce BRB permeability by targeting both its main inner and outer components through NO- and ROS-dependent pathways, offering potential treatment strategies against diabetic retinopathies.

Keywords: 16K prolactin; blood-retina barrier; diabetes; nitric oxide; oxidative stress; reactive oxygen species; retinal pigment epithelium; vasoinhibins.

Figures

Figure 1
Figure 1
Vasoinhibins prevent BK-induced increase in BRB permeability similarly to a kinin B2 receptor antagonist. (A) Evaluation of the Evans blue dye content in retinas of rats intravitreously injected 4 h earlier with PBS (Ctl), BK (1 nM), BK combined with either vasoinhibins (Vi, 1 μM) or Hoe-140 (Hoe, 3 μM), Vi alone, or Hoe alone. Values are mean ± s.e.m. normalized to the control (n = 8–16 per group; *P < 0.05). (B–D) Retinas of rats that were intravitreously injected 4 h earlier with PBS, BK, Vi, or BK combined with Vi were analyzed for kinin B2 receptor mRNA (B, mean ± s.e.m. from 5 independent experiments) and protein (C). Total β-tubulin served as loading control. (D) Quantification of kinin B2 receptor by densitometry normalized to total β-tubulin. Values correspond to the mean ± s.e.m. from 3 independent experiments. (E) Retinas of rats that were intravitreously injected 4 h earlier with PBS, BK, Vi, or BK combined with Vi were analyzed for kinin B1 receptor protein. Total knee extract from rats with Freund's adjuvant-induced arthritis (AT, arthritic tissue) was used as a positive control for B1 receptor expression. NS, not significant.
Figure 2
Figure 2
Vasoinhibins block BK-induced reduction of transendothelial resistance and morphological changes in actin cytoskeleton. Time course of trans-electrical resistance (TER) in MRCEC (A) and MBCEC (B) monolayers cultured in complete medium (Ctl) with or without 10 μM BK and 10 nM vasoinhibins (Vi). (C) TER in BUVEC monolayers cultured in complete medium (Ctl) with or without 10 μM BK and 10 nM Vi. (D) Expanded early time values of experiment (C). In (A–D), values are mean ± s.e.m. from 3 independent experiments normalized to the control; *P < 0.05 vs. Ctl. MBCEC and MRCEC were cultured on inserts with pore sizes of 0.4 μm while BUVEC cells were cultured on inserts with pore sizes of 8.0 μm. (E) BUVEC were cultured in complete medium (Ctl) with or without 10 μM BK and 10 nM Vi for 15 min and then actin cytoskeleton (F-actin) distribution was determined using rhodamine-phalloidin. Representative fields are shown. Scale bar, 10 μm.
Figure 3
Figure 3
The inhibitory effect of vasoinhibins on BK-induced reduction of transendothelial resistance and actin cytoskeleton rearrangement depends on NO. (A) Time course of TER in BUVEC monolayers cultured in complete medium (Ctl) with or without 10 μM BK and the NO synthase inhibitor L-NAME (10 mM). Values are mean ± s.e.m. from 3 independent experiments normalized to the control. *P < 0.05 vs. Ctl. (B) Rats were treated with L-NAME (1.8 mM) administered in the drinking water for 15 days, then their retinas were intravitreously injected with PBS (Ctl) or BK (1 nM), and evaluated 2 h later by the Evans blue dye assay. Values are mean ± s.e.m. normalized to control. *P < 0.05 from 8 to 16 independent observations. (C) Quantification of peak TER values (15 min after treatment start) in BUVEC monolayers cultured in complete medium (Ctl) with or without 10 μM BK and 10 nM Vi in the absence (white bars) or presence (black bars) of the NO donor DETANONOate (10 μM). *P < 0.05 from 3 independent experiments. NS, not significant. BUVEC were cultured on inserts with pore sizes of 8.0 μm. (D) BUVEC were cultured in complete medium (Ctl) with or without 10 μM BK and 10 mM L-NAME, and with the NO donor DETANONOate (10 μM) in the presence and in the absence of BK and Vi (10 nM) for 15 min, and then actin cytoskeleton (F-actin) distribution was determined using rhodamine-phalloidin. Representative fields are shown. Scale bar, 10 μm.
Figure 4
Figure 4
ROS do not participate in the vasoinhibin-mediated inhibition of transendothelial resistance reduction and actin cytoskeleton rearrangement induced by BK. (A,C) Time course of trans-electrical resistance (TER) in BUVEC monolayers cultured in complete medium (Ctl) with or without 10 μM BK and the antioxidant N-acetyl cysteine (NAC, 10 mM) or with or without 500 μM Luperox and vasoinhibins (Vi, 10 nM). BUVEC were cultured on inserts with pore sizes of 8.0 μm. (B) Corresponding quantification of TER values, 10 min after treatment initiation. Values correspond to the mean ± s.e.m. from 3 independent experiments. *P < 0.05. NS, not significant. (D) BUVEC were cultured in complete medium (Ctl) with or without 10 μM BK and 10 mM NAC or with or without 500 μM Luperox and Vi (10 nM) for 15 min, and then actin cytoskeleton (F-actin) distribution was determined using rhodamine-phalloidin. Representative fields are shown. Scale bar, 10 μm. (E) Mitochondrial membrane potential changes using JC-1 dye in BUVEC monolayers cultured in complete medium (Ctl) with or without 10 μM BK or 500 μM Luperox and 10 nM Vi. Values correspond to the mean ± s.e.m. from 3 independent experiments. *P < 0.05. NS, not significant. (F) Cytosolic levels of superoxide in BUVEC monolayers cultured in complete medium (Ctl) with or without 10 μM BK. Values correspond to the mean ± s.e.m. of 8 repeats per condition from 3 independent experiments.
Figure 5
Figure 5
BK transiently reduces ARPE-19 cell monolayer resistance and induces actin cytoskeleton rearrangement through NO, and vasoinhibins prevent these effects. (A,B) Time course of trans-electrical resistance (TER) in ARPE-19 monolayers cultured in complete medium (Ctl) with or without 10 μM BK and vasoinhibins (Vi, 10 nM) or L-NAME (10 mM). Values correspond to the mean ± s.e.m. from 3 independent experiments. *P < 0.05 vs. Ctl. (C) Quantification of peak TER values (15 min after treatment start) in ARPE-19 monolayers cultured in complete medium (Ctl) with or without 10 μM BK and 10 nM Vi in the absence (white bars) or presence (black bars) of the NO donor DETANONOate (10 μM). *P < 0.05 from 3 independent experiments. NS, not significant. ARPE-19 cells were cultured on inserts with pore sizes of 0.4 μm. (D) ARPE-19 cells were cultured in complete medium (Ctl) with or without 10 μM BK and vasoinhibins (Vi, 10 nM) or L-NAME (10 mM) or the NO donor DETANONOate (10 μM) for 15 min, and then actin cytoskeleton (F-actin) distribution was determined using rhodamine-phalloidin. Representative fields are shown. Scale bar, 10 μm.
Figure 6
Figure 6
ROS contribute to the inhibition of BK-induced decrease of ARPE-19 resistance and actin cytoskeleton rearrangement by vasoinhibins. (A,B) Time course of trans-electrical resistance (TER) in ARPE-19 monolayers cultured in complete medium (Ctl) with or without 10 μM BK and N-acetyl cysteine (NAC, 10 mM) or with or without 500 μM Luperox and vasoinhibins (Vi, 10 nM). Values correspond to the mean ± s.e.m. from 3 independent experiments. *P < 0.05 vs. Ctl. ARPE-19 cells were cultured on inserts with pore sizes of 0.4 μm. (C) ARPE-19 cells were cultured in complete medium (Ctl) with or without 10 μM BK and NAC (10 mM) or with or without 500 μM Luperox and Vi (10 nM) for 15 min, and then actin cytoskeleton (F-actin) distribution was determined using rhodamine-phalloidin. Representative fields are shown. Scale bar, 10 μm. (D) Mitochondrial membrane potential changes using JC-1 dye in ARPE-19 monolayers cultured in complete medium (Ctl) with or without 10 μM BK or 500 μM Luperox and Vi (10 nM). Values correspond to the mean ± s.e.m. from 3 independent experiments. (E) Cytosolic levels of superoxide in ARPE-19 monolayers cultured in complete medium (Ctl) with or without 10 μM BK and NAC (10 mM) or with or without 10 μM BK and Vi (10 nM). Values correspond to the mean ± s.e.m. of 4–15 repeats per condition from 3 independent experiments. *P < 0.05 vs. Ctl. NS, not significant.
Figure 7
Figure 7
Vasoinhibins reduce the retinal levels of ROS in streptozotocin-induced diabetic rats. (A) Representative images of superoxide anion production stained with dihydroethidium (DHE) on retina sections from control (Ctl) rats intravitreously injected with PBS or vasoinhibins (Vi, 1 μM) for 24 h and from streptozotocin (STZ)-induced diabetic rats intravitreously injected with PBS or Vi 24 h before the end of the 4 weeks of diabetes. Scale bar is 100 μm. (B) Fluorescence intensity of superoxide anion quantified as mean number of pixels positive for DHE staining normalized to the mean number of pixels positive for DAPI staining in the retinal pigment epithelium (RPE), outer nuclear (ONL), inner nuclear (INL), inner plexiform (IPL), and ganglion cell (GCL) layers. Data are mean ± s.e.m. of values obtained from 3 rats in each group. *P < 0.05. NS, not significant.

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