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The Angiotensin II Receptor 2 Is Expressed and Mediates Angiotensin II Signaling in Lung Fibrosis

¹ University of Giessen Lung Center, Department of Medicine, Giessen; and ² Department of Radiotherapy and Oncology, Philipps-University Marburg, Marburg, Germany

Correspondence and requests for reprints should be addressed to Melanie Königshoff, M.D., University of Giessen Lung Center, Department of Medicine II, Aulweg 123, Room 6-11, D-35392 Giessen, Germany. E-mail: Melanie.Koenigshoff{at}innere.med.uni-giessen.de

Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disease unresponsive to currently available therapies. In IPF, initial alveolar epithelial cell damage leads to activation of fibroblast-(myo)fibroblasts, which deposit an increased amount of a collagen-rich extracellular matrix. Angiotensin II (ANGII) signaling, mediated via angiotensin II receptor type 1 (AGTR1) or type 2 (AGTR2), controls tissue remodeling in fibrosis, but the relevance of AGTR2 remains elusive. In the present study, we demonstrated increased expression of AGTR1 und AGTR2 in human and rodent lung tissues from patients with IPF and mice subjected to bleomycin-induced fibrosis, respectively. Both AGTR1 und AGTR2 localized to interstitial fibroblasts. Quantitative analysis of cell surface expression in primary mouse fibroblasts revealed a significant increase of AGTR2 surface expression in fibrotic fibroblasts, whereas AGTR1 surface expression levels remained similar. ANGII treatment of normal fibroblasts led to enhanced migration and proliferation, which was abrogated after pretreatment with losartan (LOS), an AGTR1 inhibitor. In contrast, in fibrotic fibroblasts, migration and proliferation was modified only by AGTR2, but not AGTR1 inhibition (using PD123319). ANGII-induced effects were mediated via phosphorylation of the mitogen-activated protein kinases p38 and p42/44, which was blocked via LOS and PD123319, respectively. Similar effects of AGTR1 and AGTR2 inhibition were observed using conditioned media of alveolar epithelial cells, a prominent source of ANGII in the lung in vivo. In summary, we conclude that ANGII signaling occurs primarily via AGTR1 in normal fibroblasts, while AGTR2-mediated effects are dominant on activated (myo)-fibroblasts, a receptor switch that may perturb epithelial–mesenchymal interaction, thereby further perpetuating fibrogenesis.

Key Words: angiotensin II • AGTR1 • AGTR2 • lung fibrosis • fibroblast function

CLINICAL RELEVANCE Angiotensin II (ANGII) is implicated in lung fibrosis. Contributions of ANGII receptor type 1 (AGTR1) and type 2 (AGTR2) are poorly defined. Our study revealed a key role of AGTR2 in lung fibrosis by controlling fibroblast migration and proliferation.

 

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