May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Prorenin Receptor Inhibition Attenuates Retinal Angiogenesis and Inflammation in the Ischemic and Diabetic Retina
Author Affiliations & Notes
  • A. G. Miller
    Immunology, Monash University, Prahran, Australia
  • R. Heine
    Immunology, Monash University, Prahran, Australia
  • G. Tan
    Immunology, Monash University, Prahran, Australia
  • C. Tikellis
    Baker Heart Institute, Prahran, Australia
  • G. Nguyen
    INSERM, College de France, France
  • J. L. Wilkinson-Berka
    Immunology, Monash University, Prahran, Australia
  • Footnotes
    Commercial Relationships  A.G. Miller, None; R. Heine, None; G. Tan, None; C. Tikellis, None; G. Nguyen, None; J.L. Wilkinson-Berka, None.
  • Footnotes
    Support  National Health and Medical Research Council (NHMRC)
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 2648. doi:
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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.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : 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.

Methods: : 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.

Results: : (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).

Conclusions: : 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.

Keywords: retinal neovascularization • diabetic retinopathy • inflammation 
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