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

Item Type:Article
Title:Interferon-gamma signaling inhibition ameliorates angiotensin II-induced cardiac damage
Creators Name:Marko, L. and Kvakan, H. and Park, J.K. and Qadri, F. and Spallek, B. and Binger, K.J. and Bowman, E.P. and Kleinewietfeld, M. and Fokuhl, V. and 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
Publisher:American Heart Association
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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