Contribution of the vascular mineralocorticoid receptor in diabetic retinal neuropathy in a mouse model of type 1 diabetes

Abstract

Purpose : Diabetic retinopathy remains a major cause of vision loss worldwide. MR pathway overactivation has been recognized in the pathogenesis of diabetic nephropathy and retinopathy. We previously showed that MR antagonism reduced retinal inflammation and edema in a rat model of type 2 diabetes. We aimed to decipher the role of vascular MR in diabetic retinopathy.

Methods : Diabetes was induced by streptozotocin (STZ) in mice with MR invalidation specifically in vascular endothelial cells (Tie2-MR-KO) or in smooth muscle cells/pericytes (SMA-MR-KO). Electroretinography was performed 2 months after STZ injection. The neuroretina was used for transcriptomic analysis. Human vascular smooth muscle cells (VSMCs) were cultured in high glucose media and treated with aldosterone alone or associated with MR antagonist to validate the MR-regulated genes in diabetic condition.

Results : We observed impairment of scotopic and photopic ERG in diabetic wild-type mice that was improved in SMA-MR-KO mice but not in Tie2-MR-KO mice. Transcriptomic analysis identified a gene encoding stanniocalcin-1 (STC1), a neuroprotective glycoprotein expressed in the smooth muscle cells. Indeed, the expression of Stc1 was significantly downregulated in the retina of diabetic wild-type mice but upregulated in the retina of diabetic SMA-MR-KO mice. In human VSMCs cultured with high glucose, aldosterone downregulated the STC1 and MR antagonist inhibited the aldosterone-induced STC1 decrease.

Conclusions : Vascular smooth muscle/pericyte MR may contribute to the neuropathy in the diabetic retina through regulation of STC1. This hypothesis will be further investigated by the injection of recombinant STC1 in wild-type mice and/or siRNA in SMA-MR-KO mice.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.