title: Interferon-γ signaling inhibition ameliorates angiotensin II-induced cardiac damage.
abstract: Angiotensin (Ang) II induces vascular injury in part by activating innate and adaptive immunity; however, the mechanisms are unclear. We investigated the role of interferon (IFN)-γ and interleukin (IL)-23 signaling. We infused Ang II into IFN-γ receptor (IFN-γR) knockout mice and wild-type controls, as well as into mice treated with neutralizing antibodies against IL-23 receptor and IL-17A. Ang II-treated IFN-γR knockout mice exhibited reduced cardiac hypertrophy, reduced cardiac macrophage and T-cell infiltration, less fibrosis, and less arrhythmogenic electric remodeling independent of blood pressure changes. In contrast, IL-23 receptor antibody treatment did not reduce cardiac hypertrophy, fibrosis, or electric remodeling despite mildly reduced inflammation. IL-17A antibody treatment behaved similarly. In the kidney, IFN-γR deficiency reduced inflammation and tubulointerstitial damage and improved glomerular filtration rate. Nonetheless, albuminuria was increased compared with Ang II-treated wild-type controls. The glomeruli of Ang II-treated IFN-γR knockout mice exhibited fewer podocytes, less nephrin and synaptopodin staining, and impaired podocyte autophagy. Thus, IFN-γ blockade, but not IL-23 receptor antibody treatment, protects from Ang II-induced cardiac damage and electric remodeling. In the kidney, IFN-γ signaling acts in a cell type-specific manner. Glomerular filtration rate is preserved in the absence of the IFN-γR, whereas podocytes may require the IFN-γR in the presence of Ang II for normal integrity and function.
authors.affiliation: Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Lajos
authors.initials: L
authors.lastname: Markó
authors.forename: Heda
authors.initials: H
authors.lastname: Kvakan
authors.forename: Joon-Keun
authors.initials: JK
authors.lastname: Park
authors.forename: Fatimunnisa
authors.initials: F
authors.lastname: Qadri
authors.forename: Bastian
authors.initials: B
authors.lastname: Spallek
authors.forename: Katrina J
authors.initials: KJ
authors.lastname: Binger
authors.forename: Edward P
authors.initials: EP
authors.lastname: Bowman
authors.forename: Markus
authors.initials: M
authors.lastname: Kleinewietfeld
authors.forename: Verena
authors.initials: V
authors.lastname: Fokuhl
authors.forename: Ralf
authors.initials: R
authors.lastname: Dechend
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Müller
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D006321:Heart / Q000187:drug effects*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D053759:Interleukin-23 / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020381:Interleukin-17; D053759:Interleukin-23; D008565:Membrane Proteins; D008840:Microfilament Proteins; C503968:Synpo protein, mouse; C113267:nephrin; D000804:Angiotensin II; D007371:Interferon-gamma