The neuroretina is a novel mineralocorticoid target: aldosterone up‐regulates ion and water channels in Müller glial cells

Abstract

Glucocorticoids reduce diabetic macular edema, but the mechanisms underlying glucocorticoid effects are imperfectly elucidated. Glucocorticoids may bind to glucocorticoid (GR) and mineralocorticoid (MR) receptors. We hypothesize that MR activation may influence retinal hydration. The effect of the MR agonist aldosterone (24 h) on ion/water channel expression (real-time PCR, Western blot, immunofluorescence) was investigated on cultured retinal Müller glial cells (RMGs, which contribute to fluid homeostasis in the retina), in Lewis rat retinal explants, and in retinas from aldosterone-injected eyes. We evidenced cell-specific expression of MR, GR, and 11-beta-hydroxysteroid dehydrogenase type II. Aldosterone significantly enhances expression of sodium and potassium channels ENaC-alpha (6.5-fold) and Kir4.1 (1.9-fold) through MR and GR occupancy, whereas aquaporin 4 (AQP4, 2.9-fold) up-regulation is MR-selective. Aldosterone intravitreous injection induces retinal swelling (24% increase compared to sham-injected eyes) and activation of RMGs. It promotes additional localization of Kir4.1 and AQP4 toward apical microvilli of RMGs. Our results highlight the mineralocorticoid-sensitivity of the neuroretina and show that aldosterone controls hydration of the healthy retina through regulation of ion/water channels expression in RMGs. These results provide a rationale for future investigations of abnormal MR signaling in the pathological retina.

Glucocorticoid receptors in the retina, Müller glia and the formation of Müller glia-derived progenitors

“…However, we cannot exclude the possibility that MCR signaling influences the formation of MGPCs. Although the MCR-preferring ligand aldosterone failed to influence FGF2/MAPK signaling in Müller glia and did not influence the proliferation of MGPCs in damaged retinas, the GCRpreferring agents that we used are known to have some affinity for MCR (Robertson et al, 2010) and MCR is likely to be expressed by Müller glia (Zhao et al, 2010). Consistent with our findings, a recent report by Anacker and colleagues (Anacker et al, 2013) indicates that low levels of cortisol, acting through MCR, increased proliferation of hippocampal progenitors and decreased neuronal differentiation whereas high levels of cortisol, acting through GCR, decreased proliferation and decreased neural differentiation.…”

“…Therefore, Dex, CpdA and RU486 act at the MCR, albeit with low affinity (Robertson et al, 2010). In addition, the MCR is known to be expressed by Müller glia in the rat retina (Zhao et al, 2010). Thus, we tested whether Mcr expression was affect by NMDA treatment, and whether the MCR-preferring ligand aldosterone influences the formation of MGPCs in NMDA-damaged retinas.…”

Neovascularization Is Attenuated With Aldosterone Synthase Inhibition in Rats With Retinopathy

“…5,7,23,38 The presence of aldosterone synthase, MR, and 11␤HSD2 in glia and ganglion cells is also of interest given the contribution of these cell types to OIR 35,36 and recent evidence that aldosterone influences ion and water channels in macroglial Müller cells. 39 In conclusion, inhibition of aldosterone synthase is equally effective at reducing the retinal neovascularization of OIR as ARB, a finding that highlights the potential of inhibiting aldosterone for the treatment of neovascular retinopathies. Whether FAD286 is as protective as ARB in other aspects of retinal pathology, such as reducing intraocular pressure, 40,41 is worth investigating in future studies.…”

“…Emerging evidence indicates that aldosterone is likely to influence retinal pathology, such as neovascularization, and also normal physiological processes, such as retinal fluid homeostasis. 39 We now await the findings of future studies to elucidate the contribution of aldosterone and the MR to not only vascular events but also glial and neuronal processes in both healthy and diseased retina.…”

Neutrophil Gelatinase-Associated Lipocalin Is a Novel Mineralocorticoid Target in the Cardiovascular System

“…1 Extrarenal pathophysiological effects of this hormone have been characterized, extending its actions to the CV system, the brain, the adipose tissue, the skin, and the eye. [2][3][4][5] Inappropriate MR activation has been shown to promote cardiac fibrosis in experimental models 6,7 The Randomized Aldactone Evaluation Study, 8 Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study, 9 and Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure 10 clinical trials have demonstrated that the addition of the MR antagonists spironolactone or eplerenone to standard care markedly reduced the overall and CV mortality in patients with left ventricular systolic dysfunction and mild or severe symptoms of chronic heart failure (HF) or with HF signs after acute myocardial infarction.…”