Identification of a retinal aldosterone system and the protective effects of mineralocorticoid receptor antagonism on retinal vascular pathology.
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.
Wilkinson-Berka
Jennifer L
JL
Department of Immunology, Monash University, Commercial Rd, Prahran, Victoria, Australia, 3004. Jennifer.Wilkinson-Berka@med.monash.edu.au
Tan
Genevieve
G
Jaworski
Kassie
K
Harbig
Jacqueline
J
Miller
Antonia G
AG
D000450:Aldosterone / Q000502:physiology* / Q000633:toxicity; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005136:Eye Proteins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005954:Glucosephosphate Dehydrogenase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018921:Leukostasis / Q000139:chemically induced / Q000517:prevention & control; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000503:physiopathology / Q000517:prevention & control*; D018384:Oxidative Stress; D010100:Oxygen / Q000633:toxicity; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000502:physiology*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D031300:Retinal Vasculitis / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D012965:Sodium Chloride / Q000633:toxicity; D013148:Spironolactone / Q000494:pharmacology / Q000627:therapeutic use*; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000068756:Valsartan; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000502:physiology
D020533:Angiogenesis Inhibitors; D047228:Angiotensin II Type 1 Receptor Blockers; D016207:Cytokines; D005136:Eye Proteins; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013777:Tetrazoles; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D013148:Spironolactone; D012965:Sodium Chloride; D000450:Aldosterone; D000068756:Valsartan; D005954:Glucosephosphate Dehydrogenase; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; D014633:Valine; D010100:Oxygen