Neovascularization Is Attenuated With Aldosterone Synthase Inhibition in Rats With Retinopathy

Abstract

Abstract-Neovascularization is a hallmark feature of retinopathy of prematurity and diabetic retinopathy. Type 1 angiotensin receptor blockade reduces neovascularization in experimental retinopathy of prematurity, known as oxygen-induced retinopathy (OIR). We investigated in OIR whether inhibiting aldosterone with the aldosterone synthase inhibitor FAD286 reduced neovascularization as effectively as angiotensin receptor blockade (valsartan). OIR was induced in neonatal Sprague-Dawley rats, and they were treated with FAD286 (30 mg/kg per day), valsartan (10 mg/kg per day), or FAD286ϩvalsartan. The cellular sources of aldosterone synthase, the mineralocorticoid receptor, and 11␤-hydroxysteroid dehydrogenase 2 were evaluated in retinal cells involved in neovascularization (primary endothelial cells, pericytes, microglia, ganglion cells, and glia). In OIR, FAD286 reduced neovascularization and neovascular tufts by 89% and 67%, respectively, and normalized the increase in vascular endothelial growth factor mRNA (1.74-fold) and protein (4.74-fold) and was as effective as valsartan and FAD286ϩvalsartan. In retina, aldosterone synthase mRNA was reduced with FAD286 but not valsartan. Aldosterone synthase was detected in microglia, ganglion cells, and glia, whereas mineralocorticoid receptor and 11␤-hydroxysteroid dehydrogenase 2 were present in all of the cell types studied. Given the location of aldosterone synthase in microglia and their contribution to retinal inflammation and neovascularization in OIR, the effects of FAD286 on microglial density were studied. The increase in microglial density (ionized calcium binding adaptor protein 1 immunolabeling) in OIR was reduced with all of the treatments. In OIR, FAD286 reduced the increase in mRNA for tumor necrosis factor-␣, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and monocyte chemoattractant molecule 1. These findings indicate that aldosterone inhibition may be a potential treatment for retinal neovascularization.

Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice

“…68,69 One possible mechanism whereby ACE2 overexpression attenuates the diabetes-associated increase of macrophage/ microglial cells ( Figure 5) is attributable to the ability of Ang(1-7) to antagonize AGTR1s (which are expressed on microglia). AGTR1 blockade with valsartan effectively decreased microglial density in a rodent model of DR. 70 Consistent with our findings, McVicar et al 65 found a significant increase of F4/80 þ microglia in the retina when compared with nondiabetic controls, after 3 and 6 months of diabetes in mice. Similarly, Muther et al 71 observed a regular distribution of F4/80 þ in the healthy mouse retina.…”

Retinal Vasculopathy Is Reduced by Dietary Salt Restriction

“…As previously reported, 23 immunolabeling for microglia with ionized binding adaptor protein-1 (Iba1) was increased in the inner retina (region from inner limiting membrane to inner plexiform layer) of OIR rats fed an NS diet compared with room air controls, and often associated with blood vessels ( Figure 3A and 3B). In OIR rats fed an LS diet, Iba1 immunolabeling was reduced compared with OIR rats fed NS ( Figure 3A and 3B).…”

“…Water Intake, Plasma Sodium, Hematocrit, and Glomerular Number in OIR As reported previously, 23 once pups began the OIR protocol at postnatal day 5, they gained less body weight than age-matched controls receiving NS (Figure VI in the online-only Data Supplement; Table I in the online-only Data Supplement). An LS diet had no effect on body weight of controls or OIR pups until postnatal day 6 when both groups gained less weight than age-matched rats receiving an NS diet.…”

“…Using a robust model of retinopathy of prematurity, known as oxygen-induced retinopathy (OIR), 12,23 we evaluated the effects of a low-salt (LS) diet on neovascularization and capillary degeneration, as well as the levels of proangiogenic markers in retina. We examined the density of microglia and Müller cell pathology, as well as breakdown of the BRB.…”

Aldosterone Modulates Endothelial Permeability and Endothelial Nitric Oxide Synthase Activity by Rearrangement of the Actin Cytoskeleton

“…[33][34][35] In this study, we observed not only cytoskeletal and tight junction rearrangement processes in response to Aldo but also changes in the distribution pattern of VE-cadherin. VE-cadherincontaining adherens junctions have been described to actively control proper tight junction formation, and the question as to what extent Aldo-induced VE-cadherin redistribution actively influences the composition and integrity of tight junctions remains to be determined.…”