Electron microscopic immunocytochemical demonstration of blood-retinal barrier breakdown in human diabetics and its association with aldose reductase in retinal vascular endothelium and retinal pigment epithelium

Abstract

Light-microscopic immunohistochemical staining for albumin has been used to localize sites of blood-retinal barrier (BRB) breakdown in ocular disorders, but the mechanism for BRB compromise cannot be resolved at this level. Using eyes up to 2 days post-mortem from normal patients or from patients with diabetic retinopathy, or other disorders known to cause BRB failure, electron-microscopic immunocytochemistry reveals focal breakdown of the inner BRB, comprised of the retinal vascular endothelium (RVE), which appears to be mediated by diffuse permeation of the RVE cells and by vesicular transport. Permeation of the retinal pigmented epithelial (RPE) cells that comprise the outer BRB also occurs, but there is no evidence of opening of tight junctions between RVE or RPE in any of the disorders evaluated. Increased aldose reductase (AR) expression in the RVE and RPE cells of diabetics as well as in the perivascular retinal astrocytes, which interact with RVE cells to establish the inner BRB, suggests that AR activity and the subsequent intracellular accumulation of sorbitol in these cell types may impair the function of the BRB in diabetes.

Tubedown associates with cortactin and controls permeability of retinal endothelial cells to albumin

“…Extravasation or leakage of serum albumin and other materials out of retinal blood vessels has been described as a marker of retinalblood-vessel damage in humans with retinopathy (Vinores et al, 1990;Vinores et al, 1993b) and has been reported in several rodent models of breakdown of the retina-blood barrier (Vinores et al, 1999;Liu et al, 2004;Tomasek et al, 2006). The breakdown of retinal-blood-barrier function has been shown to involve changes in permeability of retinal endothelial cells (Tomasek et al, 2006), and is associated with edema and thickening of retinal tissues (Gardner et al, 2002;Sander et al, 2007).…”

Molecular genetics of microvascular disease in diabetic retinopathy

“…The protein is strongly expressed in retinal pericytes and is also found in the vascular endothelium. 10 It has been postulated that 7q35 is a susceptibility region for diabetic retinopathy and nephropathy by virtue of the AR2 gene and nearby genes. 11 It is still uncertain if the AR2 gene itself is directly causative in pre-disposition to retinopathy or protection from its development.…”

Diabetic retinopathy: Some cellular, molecular and therapeutic considerations

“…135 In advanced disease, fenestration of the normally 'tight' vascular endothelial cells may occur136 and in some damaged capillaries, i.e. microaneurysms, there is complete loss of endothelial integrity.…”