Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

Abstract

Aim/hypothesis We examined whether the renin inhibitor, aliskiren, provides similar or greater protection than ACE inhibition from non-proliferative diabetic retinopathy and from the proliferative neoangiogenesis of oxygen-induced retinopathy. Methods Transgenic (mRen-2)27 rats, which overexpress mouse renin and angiotensin in extra-renal tissues, were studied. For diabetic studies, non-diabetic, diabetic (streptozotocin, 55 mg/kg), diabetic + aliskiren (10 mg kg −1 day −1 , pump), or diabetic + lisinopril (10 mg kg −1 day −1 , drinking water) rats were evaluated over 16 weeks. For oxygeninduced retinopathy studies, rats were exposed to 80% oxygen (22 h/day) from postnatal days 0 to 11, and then room air from postnatal days 12 to 18. Aliskiren (10 or 30 mg kg −1 day −1 , pump) or lisinopril (10 mg kg −1 day −1 , drinking water) was administered during retinopathy development between postnatal days 12 and 18. Results Systolic BP in diabetic (mRen-2)27 rats was reduced with 10 mg kg −1 day −1 aliskiren, but only lisinopril normalised systolic blood pressure. In diabetic (mRen-2)27 rats, 10 mg kg −1 day −1 aliskiren and lisinopril reduced retinal acellular capillaries and leucostasis to non-diabetic levels. In oxygen-induced retinopathy, neoangiogenesis and retinal inflammation (leucostasis, ED-1 immunolabelling) were partially reduced by 10 mg kg −1 day −1 aliskiren and normalised by 30 mg kg −1 day −1 aliskiren, whereas lisinopril normalised neoangiogenesis and reduced leucostasis and ED-1 immunolabelling. Aliskiren and lisinopril normalised retinal vascular endothelial growth factor expression; however, only aliskiren reduced intercellular adhesion molecule-1 to control levels. Conclusions/interpretation Aliskiren provided similar or greater retinal protection than ACE inhibition and may be a potential treatment for diabetic retinopathy.

Combined Renin Inhibition/(Pro)Renin Receptor Blockade in Diabetic Retinopathy- A Study in Transgenic (mREN2)27 Rats

“…Renin inhibition counterbalanced these phenomena, whereas (P)RR blockade on top of renin inhibition did not offer additional advantages. The protective effect of aliskiren on retinal vasculopathy and inflammation in diabetic Ren2 rats is consistent with a previous report [56]. Diabetic retinopathy is not only associated with vascular dysfunction, but also with a loss of retinal neurons [57].…”

The Vasoneuronal Effects of AT1Receptor Blockade in a Rat Model of Retinopathy of Prematurity

“…4,17,18,20,39,40 In particular, treatment with ACE inhibitors, 17 AT 1 receptor antagonists, 17,18,20,39,41 or inhibitors of other components of the RAS, such as the prorenin receptor 35 and renin, 42 all reduce angiogenesis in the retina. The results of the current study are in line with this previous work.…”

Aliskiren inhibits the renin-angiotensin system in retinal pigment epithelium cells

“…In a different study it was shown that activation of the RAS in bovine retinal endothelial cells induced cell proliferation but treatment with aliskiren did not prevent this effect (28). Other studies using aliskiren in in vivo models demonstrate some positive effects in the retina (13)(14)(15). These studies demonstrate that aliskiren is not toxic for retinal cells (endothelial and Müller), but no observation was made concerning the mechanism of action of aliskiren on the retinal RAS or specifically on the RPE cells.…”

“…(12) Aliskiren was shown to be effective in decreasing retinal ischemic damage in an experimental model. (13) Wilkinson-Berka et al compared the effectiveness of an ACE inhibitor with aliskiren in preventing pathological features in models of retinopathy (14) and concluded that aliskiren conferred a similar or greater level of protection than the ACE inhibitor, suggesting that aliskiren has potential for the treatment of retinopathies. Despite that, studies on the effect of aliskiren upon retinal cells are scarce and the mechanism of action of this drug upon the retinal RAS has not A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 5 been described so far.…”