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A. G. Miller, R. Heine, G. Tan, C. Tikellis, G. Nguyen, J. L. Wilkinson-Berka; Prorenin Receptor Inhibition Attenuates Retinal Angiogenesis and Inflammation in the Ischemic and Diabetic Retina. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2648. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The prorenin receptor, (P)RR, is implicated in the pathogenesis of diabetic complications. We evaluated whether (P)RR inhibition, [(P)RR-I], attenuates angiogenesis and inflammation in rat models of retinopathy of prematurity (ROP) and diabetes.
ROP was induced in Sprague Dawley (SD) rat pups (N=7-10/group), 80% O2 from postnatal day (P)0-P12, then room air until P18. Shams were in room air P0 to P18. Groups were; 1) shams, 2) ROP, 3) ROP+(P)RR-I (0.1mg/kg) and 4) ROP+angiotensin type 1 receptor blockade (AT1-RB, valsartan, 40mg/kg/day). Treatments were given P12 to P18. Streptozotocin diabetes was induced in 8-week-old SD rats for 1 week (N=7-10/group). Groups were; 1) Non-diabetic (ND), 2) Diabetic (D), 3) D+(P)RR-I (0.1mg/kg) and 4) D+AT1-RB (40mg/kg/day). In ROP, blood vessel profiles (BVPs) were counted in the inner retina from 6 paraffin sections/eye. Immunohistochemistry was performed for (P)RR and phospho(p)-p38MAPK, in situ hybridisation for (P)RR and quantitative PCR for (P)RR, VEGFA and ICAM-1. In ROP and diabetes, leukostasis was quantitated with rhodamine-ConcanavalinA.
(P)RR was localised to the ganglion cell layer (GCL) and inner nuclear layer (INL). In ROP, (P)RR mRNA was increased compared to sham controls (1.7±0.3 fold, P<0.05), and decreased with (P)RR-I and AT1-RB (0.8±0.1 and 1.1±0.1, P<0.05 vs ROP). BVPs which were increased in ROP compared to sham controls (19.3±1.8 vs 11.6±0.8, P<0.01), were reduced by 70% with (P)RR-I (13.0±1.4, P<0.01), and normalised with AT1-RB (11.2±0.8, P<0.01). VEGFA and ICAM-1 mRNA were doubled in ROP compared to sham control, and reduced by (P)RR-I and AT1-RB to sham levels (P<0.05 vs ROP). p-p38 MAPK immunolabelling was not observed in shams, but evident in the GCL and INL of ROP control, and was reduced in ROP+(P)RR-I. In ROP control, leukostasis was increased 6-fold compared to sham controls (P<0.01), and reduced by 60% with (P)RR-I (P<0.02). In diabetes, leukostasis was increased 7-fold in D compared to ND controls (48.7±8.2 vs 6.7±1.7, P<0.05) and reduced with PRR-I and AT1-RB to almost ND (11.8±2.2 and 16.1±3.1, P<0.01 vs D).
These findings implicate the (P)RR in pathological angiogenesis and inflammation in the ischemic retina and involves VEGF and MAPK pathways. The modulation of (P)RR by the AT-1R indicates that cross talk between these receptors may mediate the retinoprotection afforded by (P)RR-I and AT1-RB, which has implications for the treatment of proliferative retinopathies.
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