Interferon-γ Signaling Inhibition Ameliorates Angiotensin II–Induced Cardiac Damage

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 60; no. 6; pp. 1430 - 1436
• Main Authors: Markó, Lajos, Kvakan, Heda, Park, Joon-Keun, Qadri, Fatimunnisa, Spallek, Bastian, Binger, Katrina J, Bowman, Edward P, Kleinewietfeld, Markus, Fokuhl, Verena, Dechend, Ralf, Müller, Dominik N
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01.12.2012; Lippincott Williams & Wilkins
• Subjects: Angiotensin II - pharmacology; Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - drug effects; Cardiology. Vascular system; Cardiomegaly - chemically induced; Cardiomegaly - metabolism; Cardiomegaly - pathology; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Fibrosis; Heart - drug effects; Inflammation - metabolism; Inflammation - pathology; Interferon-gamma - genetics; Interferon-gamma - metabolism; Interleukin-17 - genetics; Interleukin-17 - metabolism; Interleukin-23 - genetics; Interleukin-23 - metabolism; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Medical sciences; Membrane Proteins - metabolism; Mice; Mice, Knockout; Microfilament Proteins - metabolism; Myocardium - metabolism; Myocardium - pathology; Podocytes - drug effects; Podocytes - metabolism; Podocytes - pathology; Signal Transduction - drug effects; Hypertension; Octapeptide; Arrhythmia; Heart disease; Cytokine; Peptide hormone; immune system; Cardiovascular disease; Interferon; Angiotensin II; interferon-y
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.112.199265

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.