title: Prorenin stimulates a pro-angiogenic and pro-inflammatory response in retinal endothelial cells and an M1 phenotype in retinal microglia.
abstract: Angiogenesis and inflammation are causative factors in the development of neovascular retinopathies. These processes involve the retinal endothelium and the retinal immune cells, microglia. The renin-angiotensin system contributes to retinal injury via the actions of the type 1 angiotensin receptor (AT1R). However, it has been suggested that prorenin, the initiator of the renin-angiotensin system cascade, influences retinal injury independently from the AT1R. We evaluated whether prorenin induced a pro-angiogenic and pro-inflammatory response in retinal endothelial cells and a pro-inflammatory phenotype in retinal microglia. Primary cultures of retinal endothelial cells and microglia were studied. Rat recombinant prorenin (2 nmol/L) stimulated the proliferation and tubulogenesis of retinal endothelial cells; it increased the levels of pro-angiogenic factors, vascular endothelial growth factor, angiopoietin-1, and tyrosine kinase with immunoglobulin and epidermal growth factor homology domains, and pro-inflammatory factors, intercellular adhesion molecule-1 and monocyte chemoattractant protein-1, relative to the controls. The messenger RNA levels of the (pro)renin receptor were also increased. These effects occurred in the presence of the AT1R blocker candesartan (10 μmol/L) and the renin inhibitor aliskiren (10 μmol/L). Microglia, which express the (pro)renin receptor, elicited an activated phenotype when exposed to prorenin, which was characterized by increased levels of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, tumour necrosis factor-α, interleukin-6, and interleukin-1β and by decreased levels of interleukin-10 and arginase-1 relative to controls. Candesartan did not influence the effects of prorenin on retinal microglia. In conclusion, prorenin has distinct pro-angiogenic and pro-inflammatory effects on retinal cells that are independent of the AT1R, indicating the potential importance of prorenin in retinopathy.
authors.affiliation: Department of Immunology and Pathology, Monash University, Melbourne, Vic., Australia.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.forename: Antonia G
authors.initials: AG
authors.lastname: Miller
authors.forename: Devy
authors.initials: D
authors.lastname: Deliyanti
authors.forename: David R
authors.initials: DR
authors.lastname: Berka
authors.forename: Alex
authors.initials: A
authors.lastname: Agrotis
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Campbell
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Wilkinson-Berka
mesh_terms: D000818:Animals; D002417:Cattle; D042783:Endothelial Cells / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D017628:Microglia / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000378:metabolism; D012083:Renin / Q000494:pharmacology*; D012160:Retina / Q000166:cytology* / Q000187:drug effects*; D000093342:Prorenin Receptor
chemical_list: D011956:Receptors, Cell Surface; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D012083:Renin; D000093342:Prorenin Receptor
keywords: endothelial cells; inflammation; microglia; prorenin; retinopathy