Interferon-gamma signaling inhibition ameliorates angiotensin II-induced cardiac damage

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Item Type:	Article
Title:	Interferon-gamma signaling inhibition ameliorates angiotensin II-induced cardiac damage
Creators Name:	Marko, L., Kvakan, H., Park, J.K., Qadri, F., Spallek, B., Binger, K.J., Bowman, E.P., Kleinewietfeld, M., Fokuhl, V., Dechend, R. and Mueller, D.N.
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)-{gamma} and interleukin (IL)-23 signaling. We infused Ang II into IFN-{gamma} receptor (IFN-{gamma}R) 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-{gamma}R 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-{gamma}R 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-{gamma}R knockout mice exhibited fewer podocytes, less nephrin and synaptopodin staining, and impaired podocyte autophagy. Thus, IFN-{gamma} blockade, but not IL-23 receptor antibody treatment, protects from Ang II-induced cardiac damage and electric remodeling. In the kidney, IFN-{gamma} signaling acts in a cell type-specific manner. Glomerular filtration rate is preserved in the absence of the IFN-{gamma}R, whereas podocytes may require the IFN-{gamma}R in the presence of Ang II for normal integrity and function.
Keywords:	Angiotensin II, Immune System, Hypertension, Arrhythmia, Interferon-gamma, Animals, Mice
Source:	Hypertension
ISSN:	0194-911X
Publisher:	American Heart Association
Volume:	60
Number:	6
Page Range:	1430-1436
Date:	December 2012
Official Publication:	https://doi.org/10.1161/HYPERTENSIONAHA.112.199265
PubMed:	View item in PubMed

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