Identification of a Retinal Aldosterone System and the Protective Effects of Mineralocorticoid Receptor Antagonism on Retinal Vascular Pathology

Abstract

Blockade of the renin-angiotensin-aldosterone system (RAAS) is being evaluated as a treatment for diabetic retinopathy; however, whether the mineralocorticoid receptor (MR) and aldosterone influence retinal vascular pathology is unknown. We examined the effect of MR antagonism on pathological angiogenesis in rats with oxygen-induced retinopathy (OIR). To determine the mechanisms by which the MR and aldosterone may influence retinal angiogenesis; inflammation and glucose-6-phosphate dehydrogenase (G6PD) were evaluated in OIR and cultured bovine retinal endothelial cells (BRECs) and bovine retinal pericytes (BRPs). In OIR, MR antagonism (spironolactone) was antiangiogenic. Aldosterone may mediate the pathogenic actions of MR in the retina, with 11beta-hydroxysteroid dehydrogenase type 2 mRNA being detected and with aldosterone stimulating proliferation and tubulogenesis in BRECs and exacerbating angiogenesis in OIR, which was attenuated with spironolactone. The MR and aldosterone modulated retinal inflammation, with leukostasis and monocyte chemoattractant protein-1 mRNA and protein in OIR being reduced by spironolactone and increased by aldosterone. A reduction in G6PD may be an early response to aldosterone. In BRECs, BRPs, and early OIR, aldosterone reduced G6PD mRNA, and in late OIR, aldosterone increased mRNA for the NAD(P)H oxidase subunit Nox4. A functional retinal MR-aldosterone system was evident with MR expression, translocation of nuclear MR, and aldosterone synthase expression, which was modulated by RAAS blockade. We make the first report that MR and aldosterone influence retinal vasculopathy, which may involve inflammatory and G6PD mechanisms. MR antagonism may be relevant when developing treatments for retinopathies that target the RAAS.

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

“…121 Of great interest, it has recently been suggested that, similar to what has been described in the heart, brain and vasculature, 122 the eye has a dynamic aldosterone-mineralocorticoid receptor system that has an important pathophysiological role in the development of retinal pathology. Wilkinson-Berka et al 123 , using a rat model of oxygen-induced retinopathy (OIR) that has features of premature retinopathy in humans with neovascularization, have shown that mineralocorticoid receptor antagonism with spironolactone improves retinal angiogenesis by attenuating leukostasis and decreasing proinflamatory responses. These beneficial effects of spironolactone were attributed, at least in part, to a reduction in oxidative stress.…”

“…These beneficial effects of spironolactone were attributed, at least in part, to a reduction in oxidative stress. Further observations in cultured retinal cells and in vivo in OIR suggested that reduction in oxidative stress may be secondary to a decrease in G6PD and retinal NADPH oxidase subunit Nox4 (Wilkinson-Berka et al 123 ). Together, these observations suggest that mineralocorticoid receptor antagonism may improve diabetic nephropathy and retinopathy by restoring G6PD activity and consequently reducing oxidative stress and inflammation.…”

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

“…From PD0 to PD11, pups were exposed to 80% oxygen (wt/wt) for 22 h/day and room air for 2 h/day, a process that suppresses retinal physiological angiogenesis [7,9]. On PD12, pups were placed in room air until PD18, which induces an increase in angiogenic and inflammatory factors, and neoangiogenesis [7,9].…”

“…Separate quantification was performed for central retina (0 to 1,666±166 μm from the optic disc), mid retina (1,667 to 3,050±154 μm) and peripheral retina (3, Neoangiogenesis in OIR Eyes were processed into paraffin, serially sectioned at 3 μm, and blood vessel profiles (BVPs) quantified in four non-overlapping fields of retina/section, with six sections/retina at least 60 μm apart evaluated per rat [9]. A BVP was defined as an endothelial cell or a blood vessel with a lumen.…”

“…One such pathway is the renin-angiotensin system (RAS) as there is evidence that a local RAS including renin exists within the retina [2][3][4], and that prorenin is elevated in the plasma and vitreous humour of patients with proliferative diabetic retinopathy [5,6]. Furthermore, experimental studies indicate that ACE inhibition and type 1 angiotensin receptor blockade (ARB) are protective in models of retinopathy [7][8][9][10][11]. These findings have, to some extent, been translated into clinical trials such as the DIabetic REtinopathy Candesartan Trial (DIRECT), which reported that ARB reduced the incidence of retinopathy in type 1 diabetic patients and increased regression of retinopathy in type 2 diabetic patients [12,13].…”