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Mol Endocrinol. 2013 Dec;27(12):2116-25. doi: 10.1210/me.2013-1146. Epub 2013 Nov 6.

VDR attenuates acute lung injury by blocking Ang-2-Tie-2 pathway and renin-angiotensin system.

Author information

1
Laboratory of Metabolic Disease Research and Drug Development and Shengjing Hospital, China Medical University, Shenyang, 110000, China; kong_juan@hotmail.com; Ravi Thadhani, M.P.H., Renal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114. E-mail: thadhani.ravi@mgh.harvard.edu; and Yan Chun Li, Department of Medicine, The University of Chicago, 900 East 57th Street, KCBD 9110, Chicago, Illinois 60637. E-mail: cyan@medicine.bsd.uchicago.edu.

Abstract

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.

PMID:
24196349
PMCID:
PMC3857197
DOI:
10.1210/me.2013-1146
[Indexed for MEDLINE]
Free PMC Article
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