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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / metabolism*
  • Acute Lung Injury / pathology
  • Acute Lung Injury / physiopathology
  • Angiopoietin-2 / metabolism*
  • Animals
  • Bronchoalveolar Lavage Fluid
  • Calcitriol / pharmacology
  • Capillary Permeability / drug effects
  • Endothelial Cells / metabolism
  • Gene Deletion
  • Humans
  • Inflammation Mediators / metabolism
  • Lipopolysaccharides
  • Lung / pathology
  • Mice
  • Mice, Knockout
  • Receptor, TIE-2 / metabolism*
  • Receptors, Calcitriol / metabolism*
  • Renin-Angiotensin System* / drug effects
  • Signal Transduction* / drug effects


  • Angiopoietin-2
  • Inflammation Mediators
  • Lipopolysaccharides
  • Receptors, Calcitriol
  • Receptor, TIE-2
  • Tek protein, mouse
  • Calcitriol