title: A role for angiotensin II type 1 receptors on bone marrow-derived cells in the pathogenesis of angiotensin II-dependent hypertension.
abstract: Activation of type 1 angiotensin (AT(1)) receptors causes hypertension, leading to progressive kidney injury. AT(1) receptors are expressed on immune cells, and previous studies have identified a role for immune cells in angiotensin II-dependent hypertension. We, therefore, examined the role of AT(1) receptors on immune cells in the pathogenesis of hypertension by generating bone marrow chimeras with wild-type donors or donors lacking AT(1A) receptors (BMKO). The 2 groups had virtually identical blood pressures at baseline, suggesting that AT(1) receptors on immune cells do not make a unique contribution to the determination of baseline blood pressure. By contrast, in response to chronic angiotensin II infusion, the BMKOs had an augmented hypertensive response, suggesting a protective effect of AT(1) receptors on immune cells with respect to blood pressure elevation. The BMKOs had 50% more albuminuria after 4 weeks of angiotensin II-dependent hypertension. Angiotensin II-induced pathological injury to the kidney was similar in the experimental groups. However, there was exaggerated renal expression of the macrophage chemokine monocyte chemoattractant protein 1 in the BMKO group, leading to persistent accumulation of macrophages in the kidney. This enhanced mononuclear cell infiltration into the BMKO kidneys was associated with exaggerated renal expression of the vasoactive mediators interleukin-1beta and interleukin-6. Thus, in angiotensin II-induced hypertension, bone marrow-derived AT(1) receptors limited mononuclear cell accumulation in the kidney and mitigated the chronic hypertensive response, possibly through the regulation of vasoactive cytokines.
authors.affiliation: Division of Nephrology, Department of Medicine, Box 103015, Duke University Medical Center, Durham, NC 27710, USA. crowl004@mc.duke.edu
authors.forename: Steven D
authors.initials: SD
authors.lastname: Crowley
authors.forename: Young-Soo
authors.initials: YS
authors.lastname: Song
authors.forename: Gregory
authors.initials: G
authors.lastname: Sprung
authors.forename: Robert
authors.initials: R
authors.lastname: Griffiths
authors.forename: Matthew
authors.initials: M
authors.lastname: Sparks
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.forename: James L
authors.initials: JL
authors.lastname: Burchette
authors.forename: David N
authors.initials: DN
authors.lastname: Howell
authors.forename: Eugene E
authors.initials: EE
authors.lastname: Lin
authors.forename: Benson
authors.initials: B
authors.lastname: Okeiyi
authors.forename: Johannes
authors.initials: J
authors.lastname: Stegbauer
authors.forename: Yanqiang
authors.initials: Y
authors.lastname: Yang
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Tharaux
authors.forename: Phillip
authors.initials: P
authors.lastname: Ruiz
mesh_terms: D000419:Albuminuria / Q000139:chemically induced / Q000235:genetics / Q000652:urine; D000804:Angiotensin II; D000818:Animals; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D001854:Bone Marrow Cells / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D018932:Chemokine CCL2 / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018183:Transplantation Chimera / Q000097:blood*
chemical_list: C544066:Agtr1a protein, mouse; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II