Retinal Vasculopathy Is Reduced by Dietary Salt Restriction

Abstract

Objective— Neovascularization and vaso-obliteration are vision-threatening events that develop by interactions between retinal vascular and glial cells. A high-salt diet is causal in cardiovascular and renal disease, which is linked to modulation of the renin–angiotensin–aldosterone system. However, it is not known whether dietary salt influences retinal vasculopathy and if the renin–angiotensin–aldosterone system is involved. We examined whether a low-salt (LS) diet influenced vascular and glial cell injury and the renin–angiotensin–aldosterone system in ischemic retinopathy. Approach and Results— Pregnant Sprague Dawley rats were fed LS (0.03% NaCl) or normal salt (0.3% NaCl) diets, and ischemic retinopathy was induced in the offspring. An LS diet reduced retinal neovascularization and vaso-obliteration, the mRNA and protein levels of the angiogenic factors, vascular endothelial growth factor, and erythropoietin. Microglia, which influence vascular remodeling in ischemic retinopathy, were reduced by LS as was tumor necrosis factor-α. Macroglial Müller cells maintain the integrity of the blood–retinal barrier, and in ischemic retinopathy, LS reduced their gliosis and also vascular leakage. In retina, LS reduced mineralocorticoid receptor, angiotensin type 1 receptor, and renin mRNA levels, whereas, as expected, plasma levels of aldosterone and renin were increased. The aldosterone/mineralocorticoid receptor–sensitive epithelial sodium channel alpha (ENaCα), which is expressed in Müller cells, was increased in ischemic retinopathy and reduced by LS. In cultured Müller cells, high salt increased ENaCα, which was prevented by mineralocorticoid receptor and angiotensin type 1 receptor blockade. Conversely, LS reduced ENaCα, angiotensin type 1 receptor, and mineralocorticoid receptor expression. Conclusions— An LS diet reduced retinal vasculopathy, by modulating glial cell function and the retinal renin–angiotensin–aldosterone system.

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“…injection of pentobarbital (120 mg/kg body weight; Virbac). As expected, the body weight of pups with OIR was reduced compared with room air controls [25]. dh404 had no effect on body weight (Supplementary Table S1).…”

“…To mimic phase I OIR, astrocytes were exposed to hyperoxia in a Modular Incubator Chamber (MIC101, QNA International) and the chamber flushed for 4 min with 40% O 2 , 55% N 2 and 5 % CO 2 . The chamber was immediately sealed and placed in a 37 • C incubator for 16 h. Müller cells were isolated from 6-day-old Sprague-Dawley rats and cultured as previously described [25,28,29]. To mimic phase II OIR, Müller cells were exposed to hypoxia in a Modular Incubator Chamber and the chamber flushed for 4 min with 0.5 % O 2 , 94.5 % N 2 and 5 % CO 2 .…”

“…Vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1) were measured in retina by ELISA [25]. Retina were homogenized on ice in 0.01 M sodium phosphate buffer (pH 9.5) containing protease/phosphatase inhibitor cocktail (1:100, Sigma).…”

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“…It should be noted that, in the absence of induced pathology, aldosterone per se did not promote retinal angiogenesis. Low-salt diet appeared protective for the retina in ischemic retinopathy, despite elevated plasma aldosterone (Deliyanti et al, 2014).…”

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“…23,24 The primer sequences for VEGF, angiopoietin-2, the NADPH oxidase (Nox) family of enzymes, HO-1, NQO1, TNF-a, IL-6, and intercellular adhesion molecule-1 (ICAM-1) have been reported previously. 23,25,26 Total RNA was isolated from single retina using the RNeasy mini kit (Qiagen, VIC, Australia). One lg of RNA from each retina was subjected to DNase treatment (DNA-free kit; Ambion, Carlsbad, CA, USA) and reverse transcription (First Strand cDNA synthesis kit; Roche, Basel, Switzerland).…”