Aldosterone: a mediator of retinal ganglion cell death and the potential role in the pathogenesis in normal-tension glaucoma

E Nitta,T Fujita,T Itano,A Nishiyama,F Shiraga,K Hirooka,T Nakamura,K Tenkumo

doi:10.1038/cddis.2013.240

E Nitta, T Fujita + Show 6 more

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https://doi.org/10.1038/cddis.2013.240

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Journal: Cell Death & Disease	Publication Date: Jul 1, 2013
Citations: 28	License type: cc-by

Affiliation: Kagawa University, Okayama University

Abstract

Glaucoma is conventionally defined as a chronic optic neuropathy characterized by progressive loss of retinal ganglion cells (RGCs) and optic nerve fibers. Although glaucoma is often associated with elevated intraocular pressure (IOP), significant IOP reduction does not prevent progression of the disease in some glaucoma patients. Thus, exploring IOP-independent mechanisms of RGC loss is important. We describe chronic systemic administration of aldosterone and evaluate its effect on RGCs in rat. Aldosterone was administered via an osmotic minipump that was implanted subcutaneously into the mid-scapular region. Although systemic administration of aldosterone caused RGC loss associated with thinning of the retinal nerve fiber layer without elevated IOP, the other cell layers appeared to be unaffected. After chronic administration of aldosterone, RGC loss was observed at 2 weeks in the peripheral retina and at 4 weeks in the central retina. However, administration of mineralocorticoid receptor blocker prevented RGC loss. These results demonstrate aldosterone is a critical mediator of RGC loss that is independent of IOP. We believe this rat normal-tension glaucoma (NTG) animal model not only offers a powerful system for investigating the mechanism of neurodegeneration in NTG, but can also be used to develop therapies directed at IOP-independent mechanisms of RGC loss.

Highlights

The renin–angiotensin–aldosterone system (RAAS) is a major controller of systemic blood pressure
Many studies have investigated the role of angiotensin II (Ang II) in mediating cardiovascular damage, relatively little attention has been paid to the role of aldosterone, which is the end product of the RAAS
We recently reported that the expression of angiotensin II type 1 receptor (AT1-R) in the retina is increased after ischemia-reperfusion[19,20] and that treatment with an Received 15.5.13; revised 31.5.13; accepted 03.6.13; Edited by A Verkhratsky angiotensin-converting enzyme (ACE) inhibitor, AT1-R blocker (ARB), and mineralocorticoid receptor (MR) antagonist reduced retinal ischemia-reperfusion injury.[19,21]

Summary

Introduction

The renin–angiotensin–aldosterone system (RAAS) is a major controller of systemic blood pressure Abnormal activation of this system has been postulated to participate in the occurrence of end-organ damage in hypertensive patients.[11,12] Aldosterone is a steroid hormone that elicits its effects by binding to the mineralocorticoid receptor (MR). As compared with patients with essential hypertension, patients with primary aldosteronism, in which Ang II levels are usually very low, have a higher incidence of left ventricular hypertrophy,[13] albuminuria,[14] and stroke.[15,16] experimental animal data support a role for aldosterone in mediating cardiovascular injury in the kidney and brain.[17,18].

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