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

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.

• Authors: Jun Morinaga, Tsuyoshi Kadomatsu, Keishi Miyata, Motoyoshi Endo, Kazutoyo Terada, Zhe Tian, Taichi Sugizaki, Hiroki Tanigawa, Jiabin Zhao, Shunshun Zhu, Michio Sato, Kimi Araki, Ken-ichi Iyama, Kengo Tomita, Masashi Mukoyama, Kimio Tomita, Kenichiro Kitamura, Yuichi Oike
• Journal: Kidney international (Kidney Int) Vol. 89 Issue 2 Pg. 327-41 (Feb 2016) ISSN: 1523-1755 [Electronic] United States
• PMID: 26806834 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• ANGPTL2 protein, human
• Angiopoietin-Like Protein 2
• Angiopoietin-like Proteins
• Angiopoietins
• Angptl2 protein, mouse
• Integrin alpha5beta1
• MIRN221 microRNA, human
• MicroRNAs
• TGFB1 protein, human
• Tgfb1 protein, mouse
• Transforming Growth Factor beta1

Topics

• Aged
• Aged, 80 and over
• Angiopoietin-Like Protein 2
• Angiopoietin-like Proteins
• Angiopoietins (metabolism)
• Animals
• Disease Models, Animal
• Female
• Fibrosis
• Humans
• Integrin alpha5beta1 (metabolism)
• Kidney (pathology)
• Kidney Tubules (immunology, metabolism)
• Macrophages (physiology)
• Male
• Mice
• Mice, Knockout
• MicroRNAs (metabolism)
• Middle Aged
• Renal Insufficiency, Chronic (metabolism, pathology)
• Transforming Growth Factor beta1 (metabolism)