Abstract
Diabetic retinopathy (DR) is a leading cause of blindness among working-age adults. Increased iron accumulation is associated with several degenerative diseases. However, there are no reports on the status of retinal iron or its implications in the pathogenesis of DR. In the present study, we found that retinas of type-1 and type-2 mouse models of diabetes have increased iron accumulation compared to non-diabetic retinas. We found similar iron accumulation in postmortem retinal samples from human diabetic patients. Further, we induced diabetes in HFE knockout (KO) mice model of genetic iron overload to understand the role of iron in the pathogenesis of DR. We found increased neuronal cell death, vascular alterations and loss of retinal barrier integrity in diabetic HFE KO mice compared to diabetic wildtype mice. Diabetic HFE KO mouse retinas also exhibited increased expression of inflammation and oxidative stress markers. Severity in the pathogenesis of DR in HFE KO mice was accompanied by increase in retinal renin expression mediated by G-protein-coupled succinate receptor GPR91. In light of previous reports implicating retinal renin-angiotensin system in DR pathogenesis, our results reveal a novel relationship between diabetes, iron and renin-angiotensin system, thereby unraveling new therapeutic targets for the treatment of DR.
Highlights
In the retina, there are many iron-containing proteins that are involved in the phototransduction cascade
Iron levels in serum and eye tissues were measured in type 1 and type 2 diabetic mouse models by quantifying ferritin, an iron-storage protein, which is upregulated during intracellular iron accumulation
Labile iron staining using FeRhoNox-1 fluorescent imaging probe confirmed increased Fe2+ iron accumulation in the diabetic mice (Fig. 1D) and the diabetic human (Fig. 1E) retinal sections demonstrating that retina accumulates iron during diabetes
Summary
There are many iron-containing proteins that are involved in the phototransduction cascade. Succinate-induced activation of GPR91 has been shown to regulate the expression of renin-angiotensin system[31,32]. We have reported previously that retinal iron overload induces GPR91 expression in the retinas of HFE and hemojuvelin knockout mice models of hemochromatosis, a genetic disorder of iron overload, and subsequently stimulates the production of downstream vascular endothelial growth factor (VEGF)[34,35]. We have previously reported that HFE is expressed predominantly in the basolateral membrane of the retinal pigment epithelium, and HFE knockout (KO) mice accumulate iron in the retina with significant retinal degeneration by 18 months of age[36]. We induced diabetes in HFE knockout (KO) mice to understand the mechanistic role of iron, GPR91 and renin angiotensin system in the pathogenesis of DR
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