Angiopoietin-like protein 2 increases renal fibrosis by accelerating transforming growth factor-β signaling in chronic kidney disease

Kidney Int. 2016 Feb;89(2):327-41. doi: 10.1016/j.kint.2015.12.021. Epub 2016 Jan 1.

Abstract

Renal fibrosis is a common pathological consequence of chronic kidney disease (CKD) with tissue fibrosis closely associated with chronic inflammation in numerous pathologies. However, molecular mechanisms underlying that association, particularly in the kidney, remain unclear. Here, we determine whether there is a molecular link between chronic inflammation and tissue fibrosis in CKD progression. Histological analysis of human kidneys indicated abundant expression of angiopoietin-like protein 2 (ANGPTL2) in renal tubule epithelial cells during progression of renal fibrosis. Numerous ANGPTL2-positive renal tubule epithelial cells colocalized with cells positive for transforming growth factor (TGF)-β1, a critical mediator of tissue fibrosis. Analysis of M1 collecting duct cells in culture showed that TGF-β1 increases ANGPTL2 expression by attenuating its repression through microRNA-221. Conversely, ANGPTL2 increased TGF-β1 expression through α5β1 integrin-mediated activation of extracellular signal-regulated kinase. Furthermore, ANGPTL2 deficiency in a mouse unilateral ureteral obstruction model significantly reduced renal fibrosis by decreasing TGF-β1 signal amplification in kidney. Thus, ANGPTL2 and TGF-β1 positively regulate each other as renal fibrosis progresses. Our study provides insight into molecular mechanisms underlying chronic inflammation and tissue fibrosis and identifies potential therapeutic targets for CKD treatment.

Keywords: TGF-β; chronic kidney disease; fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Angiopoietin-like Proteins
  • Angiopoietins / metabolism*
  • Animals
  • Disease Models, Animal
  • Female
  • Fibrosis
  • Humans
  • Integrin alpha5beta1 / metabolism
  • Kidney / pathology
  • Kidney Tubules / immunology
  • Kidney Tubules / metabolism
  • Macrophages / physiology
  • Male
  • Mice
  • Mice, Knockout
  • MicroRNAs / metabolism*
  • Middle Aged
  • Renal Insufficiency, Chronic / metabolism*
  • Renal Insufficiency, Chronic / pathology
  • Transforming Growth Factor beta1 / metabolism*

Substances

  • ANGPTL2 protein, human
  • Angiopoietin-like Proteins
  • Angiopoietins
  • Angptl2 protein, mouse
  • Integrin alpha5beta1
  • MIRN221 microRNA, human
  • MicroRNAs
  • TGFB1 protein, human
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta1