Mineralocorticoid receptor pathway and its antagonism in a model of diabetic retinopathy

Abstract

<p>Diabetic retinopathy remains a major cause of vision loss worldwide. Mineralocorticoid receptor (MR) pathway activation contributes to diabetic nephropathy but its role in retinopathy is unknown. In this study, we show that MR is overexpressed in the retina of type 2 diabetic Goto-Kakizaki (GK) rats and humans and, that cortisol is the MR ligand in human eyes. Lipocalin 2 and galectin 3, two biomarkers of diabetic complications regulated by MR are increased in GK and human retina. The sustained intraocular delivery of spironolactone, a steroidal mineralocorticoid antagonist, decreased the early and late pathogenic features of retinopathy in GK rats, such as retinal inflammation, vascular leakage and retinal edema through the up-regulation of genes encoding proteins known to intervene in vascular permeability such as <i>Hey1, Vldlr</i>, <i>Pten</i>, <i>Slc7a1, Tjp1, Dlg1 and Sesn2 </i>but did not decrease VEGF. Spironolactone also normalized the distribution of ion and water channels in macroglial cells. These results indicate that MR is activated in GK and human diabetic retina and that local MR antagonism could be a novel therapeutic option for diabetic retinopathy.</p>

Mineralocorticoid pathway in retinal health and diseases

“…We have recently shown that in the nonobese Goto–Kakizaki rat, a model of type 2 diabetes, the local slow release of spironolactone from biodegradable microspheres, prevented the early retinal inflammation and ion and water channels deregulations at the early stages of retinopathy and further reduced retinal oedema at later stages (1 year). The anti‐oedematous effect was not associated with decreased VEGF expression, suggesting potential synergistic effects with currently used anti‐VEGF drugs (Zhao et al, 2021).…”

“…With ageing in rats, the expression of glucocorticoid and mineralocorticoid receptors increases in the rat neural retina (Zhao et al, 2021), but whether similar increase occurs in humans is unknown. Mineralocorticoid receptor expression was also shown to fluctuate in various models of retinal diseases.…”

“…With ageing in rats, the expression of glucocorticoid and mineralocorticoid receptors increases in the rat neural retina (Zhao et al, 2021), F I G U R E 2 Schematic representation of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR/NR3C2) actions and mineralocorticoid receptor immunohistochemistry in rat and human retinas. (a) Glucocorticoid and mineralocorticoid receptor differential actions.…”

“…The retinal bioavailability of oral eplerenone is not known. In rat models of diabetes, whereas significant retinal protection was achieved when spironolactone was delivered into the vitreous, oral eplerenone was not efficient, suggesting that it does not reach the retina unless the barriers are disrupted (Zhao et al, 2021). However, when the blood–retinal barriers are disrupted or not yet functional (like in newborn animals), systemic administration of spironolactone and eplerenone can be efficient, although efficacy might be lost upon barrier functions restoration.…”

Cerrahi Menopoz ve Kronik Serebral Hipoperfüzyon Oluşturulmuş Sıçanlarda Spironolaktonun Prefrontal Korteks ve Göz Dokularında Glikojen ve Oksidatif Stres Parametreleri Üzerine Etkisi

“…Özellikle spironolakton uygulamasının anti-oksidan, anti-inflamatuar, anti-apoptotik ve anti-anjiogenik etkili olduğunu gösteren çalışmaların sayısı oldukça fazladır (18)(19)(20)(21)27). Örneğin Zhao ve ark.nın yaptığı bir çalışmada tip 2 diyabetli sıçanlarda spironolakton uygulamasının damar geçirgenliğini düzenleyen proteinlerin sentezini artırarak retinal inflamasyonu, vasküler geçirgenliği ve ödemi azalttığını sonuçta da retinopatinin erken ve geç patojenik etkilerini iyileştirdiği bildirilmiştir (38). Başka bir çalışmada ise aldosteron uygulaması sıçandaki intraoküler basıncı yükseltmeden retina sinir lifi tabakasının incelmesine ve glokomatöz optik sinir dejenerasyonuna neden olurken spironolaktonun, retinal gangliyon hücre kaybını ve dejenerasyonu önlediği bildirilmiştir (39).…”