title: Glomerular type 1 angiotensin receptors augment kidney injury and inflammation in murine autoimmune nephritis.
abstract: Studies in humans and animal models indicate a key contribution of angiotensin II to the pathogenesis of glomerular diseases. To examine the role of type 1 angiotensin (AT1) receptors in glomerular inflammation associated with autoimmune disease, we generated MRL-Faslpr/lpr (lpr) mice lacking the major murine type 1 angiotensin receptor (AT1A); lpr mice develop a generalized autoimmune disease with glomerulonephritis that resembles SLE. Surprisingly, AT1A deficiency was not protective against disease but instead substantially accelerated mortality, proteinuria, and kidney pathology. Increased disease severity was not a direct effect of immune cells, since transplantation of AT1A-deficient bone marrow did not affect survival. Moreover, autoimmune injury in extrarenal tissues, including skin, heart, and joints, was unaffected by AT1A deficiency. In murine systems, there is a second type 1 angiotensin receptor isoform, AT1B, and its expression is especially prominent in the renal glomerulus within podocytes. Further, expression of renin was enhanced in kidneys of AT1A-deficient lpr mice, and they showed evidence of exaggerated AT1B receptor activation, including substantially increased podocyte injury and expression of inflammatory mediators. Administration of losartan, which blocks all type 1 angiotensin receptors, reduced markers of kidney disease, including proteinuria, glomerular pathology, and cytokine mRNA expression. Since AT1A-deficient lpr mice had low blood pressure, these findings suggest that activation of type 1 angiotensin receptors in the glomerulus is sufficient to accelerate renal injury and inflammation in the absence of hypertension.
authors.affiliation: Department of Medicine, Division of Nephrology, Duke University Medical Center, and Durham VA Medical Center, Durham, North Carolina 27705, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Crowley
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Vasievich
authors.forename: Phillip
authors.initials: P
authors.lastname: Ruiz
authors.forename: Samantha K
authors.initials: SK
authors.lastname: Gould
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Parsons
authors.forename: A Kathy
authors.initials: AK
authors.lastname: Pazmino
authors.forename: Carie
authors.initials: C
authors.lastname: Facemire
authors.forename: Benny J
authors.initials: BJ
authors.lastname: Chen
authors.forename: Hyung-Suk
authors.initials: HS
authors.lastname: Kim
authors.forename: Trinh T
authors.initials: TT
authors.lastname: Tran
authors.forename: David S
authors.initials: DS
authors.lastname: Pisetsky
authors.forename: Laura
authors.initials: L
authors.lastname: Barisoni
authors.forename: Minolfa C
authors.initials: MC
authors.lastname: Prieto-Carrasquero
authors.forename: Marie
authors.initials: M
authors.lastname: Jeansson
authors.forename: Mary H
authors.initials: MH
authors.lastname: Foster
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Coffman
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D018925:Chemokines / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D005260:Female; D007668:Kidney / Q000293:injuries / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D009393:Nephritis / Q000209:etiology* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012084:Renin-Angiotensin System / Q000502:physiology
chemical_list: D018925:Chemokines; D016207:Cytokines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1