Abstract
Dysfunction of renin-angiotensin system (RAS) contributes to the pathogenesis of diabetic retinopathy (DR). Prorenin, the precursor of renin is highly elevated in ocular fluid of diabetic patients with proliferative retinopathy. Prorenin may exert local effects in the eye by binding to the so-called (pro)renin receptor ((P)RR). Here we investigated the combined effects of the renin inhibitor aliskiren and the putative (P)RR blocker handle-region peptide (HRP) on diabetic retinopathy in streptozotocin (STZ)-induced diabetic transgenic (mRen2)27 rats (a model with high plasma prorenin levels) as well as prorenin stimulated cytokine expression in cultured Müller cells. Adult (mRen2)27 rats were randomly divided into the following groups: (1) non-diabetic; (2) diabetic treated with vehicle; (3) diabetic treated with aliskiren (10 mg/kg per day); and (4) diabetic treated with aliskiren+HRP (1 mg/kg per day). Age-matched non-diabetic wildtype Sprague-Dawley rats were used as control. Drugs were administered by osmotic minipumps for three weeks. Transgenic (mRen2)27 rat retinas showed increased apoptotic cell death of both inner retinal neurons and photoreceptors, increased loss of capillaries, as well as increased expression of inflammatory cytokines. These pathological changes were further exacerbated by diabetes. Aliskiren treatment of diabetic (mRen2)27 rats prevented retinal gliosis, and reduced retinal apoptotic cell death, acellular capillaries and the expression of inflammatory cytokines. HRP on top of aliskiren did not provide additional protection. In cultured Müller cells, prorenin significantly increased the expression levels of IL-1α and TNF-α, and this was completely blocked by aliskiren or HRP, their combination, (P)RR siRNA and the AT1R blocker losartan, suggesting that these effects entirely depended on Ang II generation by (P)RR-bound prorenin. In conclusion, the lack of effect of HRP on top of aliskiren, and the Ang II-dependency of the ocular effects of prorenin in vitro, argue against the combined application of (P)RR blockade and renin inhibition in diabetic retinopathy.
Highlights
Diabetic retinopathy (DR) is the most common diabetic microvascular complication and the leading cause of severe vision loss in people under the age of sixty [1]
The prevalence of DR increases with the duration of diabetes, and most individuals with type 1 diabetes and more than 60% of those with type 2 diabetes have some form of retinopathy after 20 years [2,3]
Aliskiren lowered mean arterial pressure (MAP) in Ren2 rats from 12364 mmHg to 10465 mm Hg, and this effect was unaltered by simultaneous administration of handle-region peptide (HRP) [47]
Summary
Diabetic retinopathy (DR) is the most common diabetic microvascular complication and the leading cause of severe vision loss in people under the age of sixty [1]. Hyperactivity of the renin-angiotensin system (RAS), resulting in elevated concentrations of its principal effector peptide, angiotensin (Ang) II, plays a key role in activating pathways leading to increased vascular inflammation, oxidative stress, endothelial dysfunction and tissue remodeling in variety of conditions, including diabetes and its associated complications [5,6]. The RAS was classically considered a circulating system having general systemic effects, it is recognized that there are local tissue RASs, for instance in the retina [7]. Activation of such local RASs may contribute to endorgan damage in diabetes and associated complications [7,8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
