Key result
Aliskiren treatment of diabetic (mRen2)27 rats reduced retinal apoptotic cell death, acellular capillaries, and inflammatory cytokine expression, with no additional protection provided by the addition of HRP.
Why the study?
Does combined renin inhibition and (pro)renin receptor blockade improve diabetic retinopathy in transgenic (mRen2)27 rats compared to vehicle?
Does combined renin inhibition and (pro)renin receptor blockade improve diabetic retinopathy in transgenic (mRen2)27 rats compared to vehicle?
Renin inhibition with aliskiren alleviates diabetic retinopathy in a transgenic rat model, but the addition of a (pro)renin receptor blocker (HRP) provides no further benefit.
Aliskiren attenuates retinal damage in diabetic rats without added HRP benefit; leaves open clinical translation and (P)RR role.
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.
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Batenburg et al. (2014) studied Diabetic Retinopathy (n=37). Aliskiren alone or combined with handle-region peptide (HRP) vs. Vehicle (saline) was evaluated on Retinal apoptotic cell death, acellular capillaries, and inflammatory cytokine expression. Aliskiren treatment of diabetic (mRen2)27 rats reduced retinal apoptotic cell death, acellular capillaries, and inflammatory cytokine expression, with no additional protection provided by the addition of HRP.
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