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J. L. Wilkinson-Berka, G. Tan, K. Jaworski, A. G. Miller; Aldosterone Promotes Angiogenesis and Inflammation in Ischemic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3875.
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Angiotensin II blockade is being evaluated as a treatment for diabetic retinopathy. We examined whether aldosterone, a down-stream product of angiotensin II and a potent stimulator of fibrovascular pathology, influences retinopathy of prematurity (ROP) and diabetic retinopathy.
Bovine retinal endothelial cells (BRECs) and bovine retinal pericytes (BRPs) were cultured with aldosterone for 2 hours. ROP was induced in Sprague Dawley rats (80%/20% O2 postnatal day (P)0-11, room air P12-18). Shams were in room air. ROP groups were 1) control, 2) mineralocorticoid receptor (MR) antagonist, spironolactone (Sp, 20mg/kg/day, gavage), 3) angiotensin type 1 receptor blockade (AT1-RB, gavage), valsartan (Val, 40mg/kg/day, gavage), 4) 1% NaCl (low salt, drinking water), 5) 1% NaCl+Sp, 6) 1% NaCl+Val, 7) aldosterone (0.75microg/hr, pump), 8) aldosterone-salt, 9) aldosterone-salt+Sp and 10) aldosterone-salt+Val. Treatments were between P12-18 with 7-10 rats/group. Adult rat groups were 1) non-diabetic control, 2) streptozotocin diabetes control, 3) diabetic+MR antagonist, eplerenone (100mg/kg/day, gavage) and 4) diabetic+Val (40mg/kg/day, gavage). Rats were treated for 1 week with 9 rats/group. Blood vessels were quantitated in the inner retina (6 paraffin 3 micron sections, 60 microns apart) and leukostasis in whole retina following in vivo perfusion with ConcanavalinA. Vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1) and aldosterone synthase were measured by real-time PCR, and MR by immunohistochemistry.
MR immunolabelling was detected in neurons, glia, BRECs and BRPs. In BRECs, aldosterone induced MR translocation, proliferation and tubulogenesis. These findings translated into ROP, where aldosterone-salt was pro-angiogenic and Sp and Val, anti-angiogenic. VEGF mRNA was reduced with Val but not Sp. Leukocytes and MCP-1 are implicated in vascular remodeling in the retina. In ROP, leukostasis and MCP-1 mRNA were increased with aldosterone-salt and reduced with Sp and Val. Similarly, in diabetes, leukostasis was reduced with eplerenone and Val. Aldosterone synthase mRNA was expressed in retina and up-regulated by low salt and hyperglycaemia and down-regulated by AT1-RB and MR antagonism.
To our knowledge we make the first report of a functional retinal aldosterone system and identify a previously unrecognised pathogenic role for aldosterone in ROP and diabetic retinopathy. These findings indicate that MR antagonism may be relevant when considering therapies for ischemic retinopathies which target the renin-angiotensin system.
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