title: Direct pro-inflammatory effects of prorenin on microglia.
abstract: Neuroinflammation has been implicated in hypertension, and microglia have been proposed to play an important role in the progression of this disease. Here, we have studied whether microglia are activated within cardiovascular regulatory area(s) of the brain during hypertension, especially in high blood pressure that is associated with chronic activation of the renin-angiotensin-system. In addition, we determined whether prorenin, an essential component of the renin-angiotensin-system, exerts direct pro-inflammatory effects on these microglia. Our data indicate that two rodent models which display neurogenic hypertension and over activation of the renin-angiotensin-system in the brain (sRA mice and spontaneously hypertensive rats) exhibit microglial activation, and increased levels of pro-inflammatory cytokines, in the paraventricular nucleus of the hypothalamus, an area crucial for regulation of sympathetic outflow. Further, the renin-angiotensin-system component prorenin elicits direct activation of hypothalamic microglia in culture and induction of pro-inflammatory mechanisms in these cells, effects that involve prorenin receptor-induced NFκB activation. In addition, the prorenin-elicited increases in cytokine expression were fully abolished by microglial inhibitor minocycline, and were potentiated by pre-treatment of cells with angiotensin II. Taken together with our previous data which indicate that pro-inflammatory processes in the paraventricular nucleus are involved in the hypertensive action of renin-angiotensin-system, the novel discovery that prorenin exerts direct stimulatory effects on microglial activation and pro-inflammatory cytokine production provides support for the idea that renin-angiotensin-system -induced neurogenic hypertension is not restricted to actions of angiotensin II alone.
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, Florida, United States of America; Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Peng
authors.initials: P
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, Roy J & Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Grobe
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Fiona A
authors.initials: FA
authors.lastname: Desland
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Guannan
authors.initials: G
authors.lastname: Zhou
authors.affiliation: Department of Biomedical Science, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Xiao Z
authors.initials: XZ
authors.lastname: Shen
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, Florida, United States of America; Department of Kinesiology and Integrative Physiology, Michigan Technological University, Houghton, Michigan, United States of America.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Shan
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Meng
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Mohan K
authors.initials: MK
authors.lastname: Raizada
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Colin
authors.initials: C
authors.lastname: Sumners
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D006973:Hypertension / Q000209:etiology / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D008911:Minocycline / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D012083:Renin / Q000378:metabolism* / Q000494:pharmacology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D000804:Angiotensin II; D012083:Renin; D018631:ras Proteins; D008911:Minocycline