VDR Attenuates Acute Lung Injury by Blocking Ang-2-Tie-2 Pathway and Renin-Angiotensin System

• Published in: Molecular endocrinology (Baltimore, Md.) Md.), 2013-12, Vol.27 (12), p.2116-2125
• Main Authors: Kong, Juan, Zhu, Xiangdong, Shi, Yongyan, Liu, Tianjing, Chen, Yunzi, Bhan, Ishir, Zhao, Qun, Thadhani, Ravi, Li, Yan Chun
• Format: Article
• Language: English
• Subjects: Acute Lung Injury - metabolism; Acute Lung Injury - pathology; Acute Lung Injury - physiopathology; Angiopoietin-2 - metabolism; Animals; Biological and medical sciences; Bronchoalveolar Lavage Fluid; Calcitriol - pharmacology; Capillary Permeability - drug effects; Endothelial Cells - metabolism; Fundamental and applied biological sciences. Psychology; Gene Deletion; Humans; Inflammation Mediators - metabolism; Lipopolysaccharides; Lung - pathology; Mice; Mice, Knockout; Original Research; Receptor, TIE-2 - metabolism; Receptors, Calcitriol - metabolism; Renin-Angiotensin System - drug effects; Signal Transduction - drug effects; Vertebrates: endocrinology
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2013-1146

Acute lung injury (ALI) is a hallmark of systemic inflammation associated with high mortality. Although the vitamin D receptor (VDR) is highly expressed in the lung, its role in lung physiology remains unclear. We investigated the effect of VDR deletion on ALI using a lipopolysaccharide (LPS)-induced sepsis model. After LPS challenge VDR-null mice exhibited more severe ALI and higher mortality compared with wild-type (WT) counterparts, manifested by increased pulmonary vascular leakiness, pulmonary edema, apoptosis, neutrophil infiltration, and pulmonary inflammation, which was accompanied by excessive induction of angiopoietin (Ang)-2 and myosin light chain (MLC) phosphorylation in the lung. 1,25-Dihydroxyvitamin D blocked LPS-induced Ang-2 expression by blocking nuclear factor-κB activation in human pulmonary artery endothelial cells. The severity of lung injury seen in VDR-null mice was ameliorated by pretreatment with L1–10, an antagonist of Ang-2, suggesting that VDR signaling protects the pulmonary vascular barrier by targeting the Ang-2-Tie-2-MLC kinase cascade. Severe ALI in VDR-null mice was also accompanied by an increase in pulmonary renin and angiotensin II levels, and pretreatment of VDR-null mice with angiotensin II type 1 receptor blocker losartan partially ameliorated the severity of LPS-induced lung injury. Taken together, these observations provide evidence that the vitamin D-VDR signaling prevents lung injury by blocking the Ang-2-Tie-2-MLC kinase cascade and the renin-angiotensin system.