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Endothelial dysfunction is a superinducer of syndecan-4: fibrogenic role of its ectodomain

Authors
 Mark Lipphardt  ;  Jong W. Song  ;  Brian B. Ratliff  ;  Hassan Dihazi  ;  Gerhard A. Müller  ;  Michael S. Goligorsky 
Citation
 AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, Vol.314(3) : H484-H496, 2018 
Journal Title
 AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY 
ISSN
 0363-6135 
Issue Date
2018
MeSH
• Animals ; Cells, Cultured ; Disease Models, Animal ; Endothelial Cells/metabolism* ; Endothelial Cells/pathology ; Endothelium, Vascular/metabolism* ; Endothelium, Vascular/pathology ; Endothelium, Vascular/physiopathology ; Fibrosis ; Glycocalyx/metabolism ; Hyperplasia ; Kidney/blood supply* ; Kidney/metabolism ; Kidney/pathology ; Kidney Diseases/genetics ; Kidney Diseases/metabolism* ; Kidney Diseases/pathology ; Kidney Diseases/physiopathology ; Mice, Knockout ; Microvessels/metabolism* ; Microvessels/pathology ; Microvessels/physiopathology ; Myofibroblasts/metabolism ; Myofibroblasts/pathology ; NF-kappa B/metabolism ; Oxidative Stress ; Protein Domains ; Signal Transduction ; Sirtuin 1/deficiency ; Sirtuin 1/genetics ; Syndecan-4/metabolism* ; Ureteral Obstruction/metabolism ; Ureteral Obstruction/pathology
Keywords
endothelial glycocalyx ; sirtuin 1 ; tubulointerstitial fibrosis ; vascular endothelium
Abstract
Syndecan-4 (Synd4) is a member of the membrane-spanning, glycocalyx-forming proteoglycan family. It has been suggested that Synd4 participates in renal fibrosis. We compared wild-type and fibrosis-prone endothelial sirtuin 1-deficient (Sirt1endo-/-) mice, the latter being a model of global endothelial dysfunction. We performed mass spectrometry analysis, which revealed that Synd4 was highly enriched in the secretome of renal microvascular endothelial cells obtained from Sirt1endo-/- mice upon stimulation with transforming growth factor-β1; notably, all detectable peptides were confined to the ectodomain of Synd4. Elevated Synd4 was due to enhanced NF-κB signaling in Sirt1endo-/- mice, while its shedding occurred as a result of oxidative stress in Sirt1 deficiency. Synd4 expression was significantly enhanced after unilateral ureteral obstruction compared with contralateral kidneys. Furthermore, hyperplasia of renal myofibroblasts accompanied by microvascular rarefaction and overexpression of Synd4 were detected in Sirt1endo-/- mice. The ectodomain of Synd4 acted as a chemoattractant for monocytes with higher levels of macrophages and higher expression levels of Synd4 in the extracellular matrix of Sirt1endo-/- mice. In vitro, ectodomain application resulted in generation of myofibroblasts from cultured renal fibroblasts, while in vivo, subcapsular injection of ectodomain increased interstitial fibrosis. Moreover, the endothelial glycocalyx was reduced in Sirt1endo-/- mice, highlighting the induction of Synd4 occurring in parallel with the depletion of its intact form and accumulation of its ectodomain in Sirt1endo-/- mice. On the basis of our experimental results, we propose that it is the Synd4 ectodomain per se that is partially responsible for fibrosis in unilateral ureteral obstruction, especially when it is combined with endothelial dysfunction. NEW & NOTEWORTHY Our findings suggest that endothelial dysfunction induces the expression of syndecan-4 via activation of the NF-κB pathway. Furthermore, we show that syndecan-4 is shed to a greater amount because of increased oxidative stress in dysfunctional endothelial cells and that the release of the syndecan-4 ectodomain leads to tubulointerstitial fibrosis.
Files in This Item:
T201806193.epub Download
DOI
10.1152/ajpheart.00548.2017
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Anesthesiology and Pain Medicine (마취통증의학교실) > 1. Journal Papers
Yonsei Authors
Song, Jong Wook(송종욱) ORCID logo https://orcid.org/0000-0001-7518-2070
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/172984
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