title: Angiopoietin-2-induced arterial stiffness in CKD.
abstract: The mechanism of vascular calcification in CKD is not understood fully, but may involve collagen deposition in the arterial wall upon osteo/chondrocytic transformation of vascular smooth muscle cells (VSMCs). Increased levels of circulating angiopoietin-2 correlate with markers of CKD progression and angiopoietin-2 regulate inflammatory responses, including intercellular and vascular adhesion and recruitment of VSMCs. Here, we investigate the potential role of angiopoietin-2 in the pathogenesis of arterial stiffness associated with CKD. In a cohort of 416 patients with CKD, the plasma level of angiopoietin-2 correlated independently with the severity of arterial stiffness assessed by pulse wave velocity. In mice subjected to 5/6 subtotal nephrectomy or unilateral ureteral obstruction, plasma levels of angiopoietin-2 also increased. Angiopoietin-2 expression markedly increased in tubular epithelial cells of fibrotic kidneys but decreased in other tissues, including aorta and lung, after 5/6 subtotal nephrectomy. Expression of collagen and profibrotic genes in aortic VSMCs increased in mice after 5/6 subtotal nephrectomy and in mice producing human angiopoietin-2. Angiopoietin-2 stimulated endothelial expression of chemokines and adhesion molecules for monocytes, increased Ly6C(low) macrophages in aorta, and increased the expression of the profibrotic cytokine TGF-β1 in aortic endothelial cells and Ly6C(low) macrophages. Angiopoietin-2 blockade attenuated expression of monocyte chemokines, profibrotic cytokines, and collagen in aorta of mice after 5/6 subtotal nephrectomy. This study identifies angiopoietin-2 as a link between kidney fibrosis and arterial stiffness. Targeting angiopoietin-2 to attenuate inflammation and collagen expression may provide a novel therapy for cardiovascular disease in CKD.
authors: Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan; Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Chu-Tung Branch, Hsin-Chu, Taiwan; and.
authors: Fan-Chi
authors: FC
authors: Chang
authors: Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan;
authors: Wen-Chih
authors: WC
authors: Chiang
authors: Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan;
authors: Ming-Hsuan
authors: MH
authors: Tsai
authors: Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan; Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan.
authors: Yu-Hsiang
authors: YH
authors: Chou
authors: Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan.
authors: Szu-Yu
authors: SY
authors: Pan
authors: Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan;
authors: Yu-Ting
authors: YT
authors: Chang
authors: Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan;
authors: Pei-Ying
authors: PY
authors: Yeh
authors: Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan; Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan;
authors: Yi-Ting
authors: YT
authors: Chen
authors: Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan;
authors: Chih-Kang
authors: CK
authors: Chiang
authors: Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan.
authors: Yung-Ming
authors: YM
authors: Chen
authors: Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan;
authors: Tzong-Shinn
authors: TS
authors: Chu
authors: Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan;
authors: Kwan-Dun
authors: KD
authors: Wu
authors: Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan; Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; linsl@ntu.edu.tw.
authors: Shuei-Liong
authors: SL
authors: Lin
mesh_terms: D000368:Aged; D042683:Angiopoietin-1 / Q000097:blood / Q000378:metabolism*; D042702:Angiopoietin-2 / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D003430:Cross-Sectional Studies; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D005355:Fibrosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D042787:Receptor, TIE-2 / Q000097:blood; D051436:Renal Insufficiency, Chronic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D059467:Transcriptome / Q000276:immunology / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D059289:Vascular Stiffness / Q000276:immunology / Q000502:physiology*
chemical_list: C467630:ANGPT1 protein, human; C586513:ANGPT2 protein, human; D042683:Angiopoietin-1; D042702:Angiopoietin-2; C467628:Angpt1 protein, mouse; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D003094:Collagen; D042787:Receptor, TIE-2