Over-Expression of (pro)renin Receptor in Mouse Retina Induces a Breakdown of Blood-Retinal-Barrier

Abstract

Purpose: : Highly increased plasma and vitreous prorenin is a biomarker of diabetic retinopathy. Prorenin has long been thought to be an inactive form of renin, a protease that cleaves angiotensinogen into angiotensin I, the rate-limiting step in the cascade generating angiotensin. Recent studies have shown that both renin and prorenin can bind to a new identified receptor, (pro)renin receptor (PRR). PRR-bound prorenin is enzymatically active thus increasing the production of angiotensin. Further more, the binding of (pro)renin to PRR directly triggers intracellular signaling pathways independent of angiotensin generation. In this study, we investigate the role of this pathway in the retina.

Methods: : RPP expression in the adult and developing retina was examined by immunocytochemistry and immunofluorescence. To test the effect of PRR on retinal function, a human PRR was expressed in the retina of wild-type C57BL/6 mice through intravitreal injection of AAV vector. An AAV vector expressing a soluble form of RPP lacking the transmembrane and cytoplasmic domains was also used. Retinal vasculature was evaluated by fluorescein angiography, permeability assays and immunocytochemistry and immunofluorescence.

Results: : We found that PRR is expressed in the retinal vessels in normal C57BL/6 mice. Over-expression of PRR via AAV-mediated gene delivery causes severe retinal vascular leakage. However, this effect is not observed in eyes received injection of AAV vectors carrying genes encoding the soluble form of PRR or Angiotensin II. These findings suggest that increased retinal vascular permeability is likely mediated by direct RPP activation independent the action of Angiotensin II.

Conclusions: : PRR is expressed in the retinal vessels. Over-expression of RPP leads to a breakdown of the blood-retinal barrier. The effect of RPP is likely mediated by direct receptor activation independent of Angiotensin II signaling pathways. These results implicate PRR may play a role in retinal vascular function. Further studies are under going to elucidate the underlying mechanisms of PRR in retinal vascular function and in pathogenesis of diabetic retinopathy.

Keywords: gene transfer/gene therapy • retina • pathology: experimental