Purchase this article with an account.
Roksana Armani, Alex Agrotis, Jennifer Wilkinson-Berka; Are hypoxia and succinate mediators of renin-angiotensin system related vascular injury in the retina?. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5602.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Blockade of the angiotensin type 1 receptor (ARB) reduces vasculopathy in animal models of diabetic retinopathy and retinopathy of prematurity, however, whilst ARB has benefits in patients with diabetic retinopathy, it is not completely protective. We suggest that a possible reason for this shortfall is our lack of understanding about the factors which activate the retinal renin-angiotensin system (RAS), and the pathological pathways with which the RAS interacts to promote retinopathy. Increases in tissue hypoxia and succinate are likely candidates, as they are known to increase renin secretion in kidney, and also to stimulate VEGF production in retinal ganglion cells (RGC) and subsequent retinal neovascularization. We aimed to determine whether RGCs exposed to hypoxia and succinate increased production of angiogenic factors and oxidative stress elements, and whether these events were modulated by the RAS.
Primary rat RGCs were cultured from 3-day-old Sprague Dawley rat pups and treated with hypoxia (1% O2) and succinate (10 μM) for 2 to 4 hours. RGCs cultured under these conditions were treated with the ARB, valsartan (10 ρmol). Comparisons were made to normoxic and untreated controls. The expression levels of specific angiogenic factors, NADPH oxidase (NOX) isoforms 1, 2 and 4, and RAS components were evaluated. Experiments were conducted 3-4 times in triplicate.
Both hypoxia and succinate increased the mRNA levels of VEGF and angiopoietin1, which were reduced to control levels with valsartan. Angiotensin II is a potent stimulator of NOX, whose down-stream targets include oxidative stress-mediated increases in VEGF. In RGCs, NOX1 and NOX2 mRNA levels were increased by hypoxia, while NOX4 mRNA levels were increased by succinate. Interestingly, in RGCs exposed to succinate, valsartan markedly increased renin expression and NOX1 mRNA, yet had no effect on NOX2 mRNA and reduced NOX4 mRNA levels.
That changes in RGC metabolism induced by hypoxia and succinate stimulate the production of angiogenic and oxidative stress elements, which can be blunted by RAS blockade. The failure of ARB to reduce NOX1 expression coupled with a rise in renin, suggests that interactions between the RAS and NOX1 in RGCs may partly explain the non-complete protective effect of ARB treatment in diabetic retinopathy.
This PDF is available to Subscribers Only