title: RILLKKMPSV influences the vasculature, neurons and glia, and (pro)renin receptor expression in the retina.
abstract: The (pro)renin receptor [(P)RR] is implicated in organ pathology. We examined the cellular location of the (P)RR and whether a putative (P)RR antagonist, RILLKKMPSV, corresponding to the handle region of the prorenin prosegment (handle region peptide [HRP]) influences angiogenesis, inflammation, and neuronal and glial function in rat retina. The (P)RR was localized to retinal vessels, endothelial cells, and pericytes, but most immunolabeling was in ganglion cells and glia. HRP (1 mg/kg per day by IP injection) reduced physiological angiogenesis in developing retina. Moreover, HRP (0.1 mg/kg per day by subcutaneous minipump) reduced pathological retinal angiogenesis, inflammation, and vascular endothelial growth factor and intercellular adhesion molecule-1 mRNA in rats with oxygen-induced retinopathy (OIR) to an extent similar to valsartan (10 mg/kg per day, IP). In contrast to its effects on vasculature, HRP compromised the electroretinogram in shams and OIR and increased phosphorylated extracellular-signal-related protein kinase 1/2 immunolabeling in shams but not in OIR, whereas valsartan did not affect the electroretinogram and reduced extracellular-signal-related protein kinase 1/2 immunolabeling in OIR. Retinal (P)RR mRNA levels were increased in OIR; HRP, but not valsartan, increased (P)RR mRNA levels in shams, whereas both HRP and valsartan reduced (P)RR mRNA levels in OIR. A control peptide (VSPMKKLLIR, 0.1 mg/kg per day) did not influence retinal vasculopathy or function. Circulating HRP levels in rats administered 1 mg/kg per day HRP were undetectable (<3 pmol/L). We conclude that HRP had protective effects on the retinal vasculature similar to those of valsartan; however, unlike valsartan, HRP injured neuro-glia, which may involve the (P)RR, although the undetectable circulating HRP level makes a direct effect of HRP on retinal (P)RR function unlikely.
authors.affiliation: Department of Immunology, Monash University, Melbourne, Victoria, Australia. jennifer.wilkinson-berka@med.monash.edu.au
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Wilkinson-Berka
authors.forename: Ronen
authors.initials: R
authors.lastname: Heine
authors.forename: Genevieve
authors.initials: G
authors.lastname: Tan
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Kate M
authors.initials: KM
authors.lastname: Hatzopoulos
authors.forename: Erica L
authors.initials: EL
authors.lastname: Fletcher
authors.forename: Katrina J
authors.initials: KJ
authors.lastname: Binger
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Campbell
authors.forename: Antonia G
authors.initials: AG
authors.lastname: Miller
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival; D012085:Chymosin; D004195:Disease Models, Animal; D004792:Enzyme Precursors; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology; D011336:Probability; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012016:Reference Values; D012160:Retina / Q000378:metabolism*; D012164:Retinal Diseases / Q000235:genetics / Q000503:physiopathology*; D012171:Retinal Vessels / Q000187:drug effects* / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D000093342:Prorenin Receptor
chemical_list: D004792:Enzyme Precursors; D009842:Oligopeptides; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D013777:Tetrazoles; C527127:handle-region peptide, rat; D000068756:Valsartan; C032443:prorennin; D012085:Chymosin; D014633:Valine; D000093342:Prorenin Receptor