Angiotensin type‐1 receptor inhibition is neuroprotective to amacrine cells in a rat model of retinopathy of prematurity

Abstract

Retinopathy of prematurity (ROP) is characterized by deficits in the scotopic pathway, although the cellular locus for these deficits is not clear. Here we examined neurochemical and cellular changes that develop during oxygen-induced retinopathy, a model of ROP. In addition, we examined whether treatment with the angiotensin II type-1 receptor inhibitor, valsartan, prevented these changes. Newborn Sprague-Dawley rats were exposed from postnatal day (P) 0 to 11 to 80%:20% O(2) (22:2 hr/day) and then room air until P18. Valsartan (40 mg/kg/day) was administered from P12-P18. Pattern recognition analysis of overlapping amino acid profiles was used to provide a statistically robust and spatially complete classification of neural elements for each experimental condition. Classification yielded 12 neuronal theme classes in controls and nine classes following ROP. ROP was associated with a reduction in the number of amacrine and bipolar cell theme classes. The reduction in theme classes was confirmed as true neuronal loss by quantifying anatomical changes and using an apoptotic marker. ROP was associated with shifts in amino acid levels across all neuronal populations except for horizontal cells. A reduction in the density of glycine-immunoreactive amacrine cells, and particularly parvalbumin-immunoreactive AII amacrine cells, was observed following ROP. Valsartan treatment during ROP prevented loss of theme classes and loss of AII amacrine cells. This study suggests that deficits in scotopic vision during ROP may be associated with loss of AII amacrine cells. In addition, this study highlights the potential of AT(1)R blockade in preventing neuronal anomalies in this condition.

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

“…ACE inhibition and ARB improve aspects of neuronal and glial damage in both situations [42], such as ameliorating losses in the electroretinogram [25,38,43] and neuronal and glial cell degeneration [44][45][46]. Our identification of renin in retinal Müller cells [2] and ganglion cells [3] is suggestive that aliskiren may influence these cell populations.…”

Neovascularization Is Attenuated With Aldosterone Synthase Inhibition in Rats With Retinopathy

“…1 The renin-angiotensin-aldosterone system (RAAS) is implicated in the development of retinal neovascularization, given that a local RAAS exists within the retina, [3][4][5] which is upregulated in both ROP and diabetic retinopathy. 6 -8 Furthermore, blockade of angiotensin II with either angiotensin-converting enzyme (ACE) inhibitors or type 1 angiotensin receptor blockers (ARB) have beneficial effects on microvascular injury in experimental ROP 7,9 and diabetic retinopathy. 10 -13 These protective effects have, to some extent, been translated to clinical studies of diabetic retinopathy, 14 -16 although other randomized, controlled clinical trials have reported ACE inhibition to be ineffective 17 or not superior to other blood pressure-lowering therapies.…”

The Vasoneuronal Effects of AT1Receptor Blockade in a Rat Model of Retinopathy of Prematurity

“…Alterations in horizontal cells and neurochemical changes across a variety of inner retinal neurons have also been reported. 12 What is not well known is whether treatments that ameliorate the vascular pathology in OIR or ROP also prevent neuronal dysfunction and loss.…”

“…Valsartan was used to treat animals in this study because it is known to reduce retinal neovasculariazation 18,20 and partially ameliorate neuronal loss in a rat model of OIR 12 and has been shown previously to prevent retinal dysfunction in a rat model of diabetes. 22 We evaluated the effect of a range of doses of valsartan on blood vessel growth, microglial activation, and retinal function.…”