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Prorenin stimulates a pro‐angiogenic and pro‐inflammatory response in retinal endothelial cells and an M1 phenotype in retinal microglia
Author(s) -
Zhu Tong,
Miller Antonia G,
Deliyanti Devy,
Berka David R,
Agrotis Alex,
Campbell Duncan J,
WilkinsonBerka Jennifer L
Publication year - 2015
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12376
Subject(s) - retinal , endocrinology , medicine , microglia , angiogenesis , vascular endothelial growth factor , angiotensin ii , biology , microbiology and biotechnology , chemistry , inflammation , receptor , cancer research , biochemistry , vegf receptors
Summary 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 ( AT 1R). However, it has been suggested that prorenin, the initiator of the renin‐angiotensin system cascade, influences retinal injury independently from the AT 1R. 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 AT 1R blocker candesartan (10 μ mol/L) and the renin inhibitor aliskiren (10 μ mol/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‐1 β 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 AT 1R, indicating the potential importance of prorenin in retinopathy.