title: Tumor necrosis factor-α produced in the kidney contributes to angiotensin II-dependent hypertension.
abstract: Immune system activation contributes to the pathogenesis of hypertension and the resulting progression of chronic kidney disease. In this regard, we recently identified a role for proinflammatory Th1 T-lymphocyte responses in hypertensive kidney injury. Because Th1 cells generate interferon-γ and tumor necrosis factor-α (TNF-α), we hypothesized that interferon-γ and TNF-α propagate renal damage during hypertension induced by activation of the renin-angiotensin system. Therefore, after confirming that mice genetically deficient of Th1 immunity were protected from kidney glomerular injury despite a preserved hypertensive response, we subjected mice lacking interferon-γ or TNF-α to our model of hypertensive chronic kidney disease. Interferon deficiency had no impact on blood pressure elevation or urinary albumin excretion during chronic angiotensin II infusion. By contrast, TNF-deficient (knockout) mice had blunted hypertensive responses and reduced end-organ damage in our model. As angiotensin II-infused TNF knockout mice had exaggerated endothelial nitric oxide synthase expression in the kidney and enhanced nitric oxide bioavailability, we examined the actions of TNF-α generated from renal parenchymal cells in hypertension by transplanting wild-type or TNF knockout kidneys into wild-type recipients before the induction of hypertension. Transplant recipients lacking TNF solely in the kidney had blunted hypertensive responses to angiotensin II and augmented renal endothelial nitric oxide synthase expression, confirming a role for kidney-derived TNF-α to promote angiotensin II-induced blood pressure elevation by limiting renal nitric oxide generation.
authors.affiliation: From the Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, NC (J.Z., M.B.P., R.G., A.M., Y.-s.S., N.S.K., M.S., H.J., S.D.C.); Department of Biology, University of Virginia, Charlottesville (E.E.L.); and Department of Medicine, Southeast University, Nanjing, China (M.W.).
authors.forename: Jiandong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: From the Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, NC (J.Z., M.B.P., R.G., A.M., Y.-s.S., N.S.K., M.S., H.J., S.D.C.); Department of Biology, University of Virginia, Charlottesville (E.E.L.); and Department of Medicine, Southeast University, Nanjing, China (M.W.).
authors.forename: Mehul B
authors.initials: MB
authors.lastname: Patel
authors.affiliation: From the Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, NC (J.Z., M.B.P., R.G., A.M., Y.-s.S., N.S.K., M.S., H.J., S.D.C.); Department of Biology, University of Virginia, Charlottesville (E.E.L.); and Department of Medicine, Southeast University, Nanjing, China (M.W.).
authors.forename: Robert
authors.initials: R
authors.lastname: Griffiths
authors.affiliation: From the Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, NC (J.Z., M.B.P., R.G., A.M., Y.-s.S., N.S.K., M.S., H.J., S.D.C.); Department of Biology, University of Virginia, Charlottesville (E.E.L.); and Department of Medicine, Southeast University, Nanjing, China (M.W.).
authors.forename: Alice
authors.initials: A
authors.lastname: Mao
authors.affiliation: From the Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, NC (J.Z., M.B.P., R.G., A.M., Y.-s.S., N.S.K., M.S., H.J., S.D.C.); Department of Biology, University of Virginia, Charlottesville (E.E.L.); and Department of Medicine, Southeast University, Nanjing, China (M.W.).
authors.forename: Young-soo
authors.initials: YS
authors.lastname: Song
authors.affiliation: From the Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, NC (J.Z., M.B.P., R.G., A.M., Y.-s.S., N.S.K., M.S., H.J., S.D.C.); Department of Biology, University of Virginia, Charlottesville (E.E.L.); and Department of Medicine, Southeast University, Nanjing, China (M.W.).
authors.forename: Norah S
authors.initials: NS
authors.lastname: Karlovich
authors.affiliation: From the Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, NC (J.Z., M.B.P., R.G., A.M., Y.-s.S., N.S.K., M.S., H.J., S.D.C.); Department of Biology, University of Virginia, Charlottesville (E.E.L.); and Department of Medicine, Southeast University, Nanjing, China (M.W.).
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Sparks
authors.affiliation: From the Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, NC (J.Z., M.B.P., R.G., A.M., Y.-s.S., N.S.K., M.S., H.J., S.D.C.); Department of Biology, University of Virginia, Charlottesville (E.E.L.); and Department of Medicine, Southeast University, Nanjing, China (M.W.).
authors.forename: Huixia
authors.initials: H
authors.lastname: Jin
authors.affiliation: From the Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, NC (J.Z., M.B.P., R.G., A.M., Y.-s.S., N.S.K., M.S., H.J., S.D.C.); Department of Biology, University of Virginia, Charlottesville (E.E.L.); and Department of Medicine, Southeast University, Nanjing, China (M.W.).
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: From the Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, NC (J.Z., M.B.P., R.G., A.M., Y.-s.S., N.S.K., M.S., H.J., S.D.C.); Department of Biology, University of Virginia, Charlottesville (E.E.L.); and Department of Medicine, Southeast University, Nanjing, China (M.W.).
authors.forename: Eugene E
authors.initials: EE
authors.lastname: Lin
authors.affiliation: From the Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, NC (J.Z., M.B.P., R.G., A.M., Y.-s.S., N.S.K., M.S., H.J., S.D.C.); Department of Biology, University of Virginia, Charlottesville (E.E.L.); and Department of Medicine, Southeast University, Nanjing, China (M.W.). steven.d.crowley@duke.edu.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Crowley
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D006973:Hypertension / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051436:Renal Insufficiency, Chronic / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D012084:Renin-Angiotensin System / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D014409:Tumor Necrosis Factor-alpha; D014662:Vasoconstrictor Agents; D000804:Angiotensin II
keywords: angiotensin II; hypertension; interferon-gamma; kidney; tumor necrosis factor-alpha