Mineralocorticoid Receptor Pathway and Its Antagonism in a Model of Diabetic Retinopathy

Abstract

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 diabetes 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 upregulation of genes encoding proteins known to intervene in vascular permeability such as Hey1, Vldlr, Pten, Slc7a1, Tjp1, Dlg1, and Sesn2 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.

Chronic Systemic Dexamethasone Regulates the Mineralocorticoid/Glucocorticoid Pathways Balance in Rat Ocular Tissues

“…In amphibian kidney cells, dexamethasone was shown to down-regulate MR [35] and in LPS-induced uveitis model, we showed that MR down-regulation in iris/ciliary body coincided with high corticosterone levels together with an increase expression of 11β-hsd1 [32] suggesting that both endogenous and exogenous corticoids could also regulate MR expression. On the other hand, in the Goto-Kakizaki diabetic rat model, we observed both a reduced cortisone/cortisol ratio and an increased MR expression in the neural retina [36] showing that the ligand levels and the GR and MR expression levels might not be regulated in a simple manner. In our experiments, Nr3c2 was also downregulated in the neural retina of rats treated with saline, in which corticosterone levels are reduced in the ocular media and in the serum but in which no dexamethasone could influence Nr3c2 or Nr3c1 expression.…”

“…To evaluate whether the imbalance of expression in the Nr3c2/Nr3c1 and 11β-hsd1/11β-hsd2 ratio translate into transcriptional consequences, we have quantified the expression of genes known to be regulated by GR/MR pathways in the neural retina such as Scnn1A encoding the Na+ channel ENac-aplha the K+ channel Kir4.1, as well as the water channel Aqp4 [35,36]. As shown in Figure 4, the three genes were significantly down-regulated in the neural retina in rats after 5 days of dexamethasone treatment and Scnn1A and Aqp4 were significantly down-regulated also after saline injection, which is in line with the downregulation of genes encoding both GR and MR after both treatments, but without MR/GR imbalance.…”

Nonsteroidal Mineralocorticoid Receptor Antagonism by Finerenone—Translational Aspects and Clinical Perspectives across Multiple Organ Systems

“…Additionally, MR antagonism attenuated aldosterone-induced inflammation, with a reduction in leukostasis and MCP-1 levels being observed [ 117 ]. The expression of retinal MR was found to be increased in diabetic patients compared with nondiabetic controls [ 123 ], but the role of the MR in the development of diabetic retinopathy has yet to be fully elucidated. Intraocular treatment with spironolactone decreased retinal edema in Goto-Kakizaki rats with T2D by preventing retinal barrier breakdown [ 123 ].…”

“…The expression of retinal MR was found to be increased in diabetic patients compared with nondiabetic controls [ 123 ], but the role of the MR in the development of diabetic retinopathy has yet to be fully elucidated. Intraocular treatment with spironolactone decreased retinal edema in Goto-Kakizaki rats with T2D by preventing retinal barrier breakdown [ 123 ]. These rats also showed an increased expression of the inflammatory markers intercellular adhesion molecule 1 (ICAM-1) and MCP-1, which was also reversed with MR antagonism [ 123 ].…”

“…Intraocular treatment with spironolactone decreased retinal edema in Goto-Kakizaki rats with T2D by preventing retinal barrier breakdown [ 123 ]. These rats also showed an increased expression of the inflammatory markers intercellular adhesion molecule 1 (ICAM-1) and MCP-1, which was also reversed with MR antagonism [ 123 ]. Recently, two sub-studies of patients with CKD and T2D from the FIDELITY population assessed whether finerenone is able to delay the progression of diabetic retinopathy.…”