TGF-β promotes fibrosis after severe acute kidney injury by enhancing renal macrophage infiltration

被引：89
|
作者：
Chung, Sungjin [1 ,2 ,3 ]
Overstreet, Jessica M. [1 ,2 ]
Li, Yan [1 ,2 ]
Wang, Yinqiu [1 ,2 ]
Niu, Aolei [1 ,2 ]
Wang, Suwan [1 ,2 ]
Fan, Xiaofeng [1 ,2 ]
Sasaki, Kensuke [1 ,2 ]
Jin, Guan-Nan [1 ,2 ]
Khodo, Stellor Nlandu [1 ,2 ]
Gewin, Leslie [1 ,2 ]
Zhang, Ming-Zhi [1 ,2 ]
Harris, Raymond C. [1 ,2 ,4 ]
机构：
[1] Vanderbilt Univ, Sch Med, Div Nephrol & Hypertens, Dept Med, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Sch Med, Vanderbilt Ctr Kidney Dis, Nashville, TN 37232 USA
[3] Catholic Univ Korea, Coll Med, Dept Internal Med, Seoul, South Korea
[4] Dept Vet Affairs, Nashville, TN USA
来源：
JCI INSIGHT | 2018年 / 3卷 / 21期
关键词：
GROWTH-FACTOR RECEPTOR; ISCHEMIA-REPERFUSION; CELLS; CYCLOOXYGENASE-2; RECOVERY; POLARIZATION; NEPHROPATHY; INHIBITION; EXPRESSION; DELETION;
D O I：
10.1172/jci.insight.123563
中图分类号：
R-3 [医学研究方法]; R3 [基础医学];
学科分类号：
1001 ;
摘要：
TGF-beta signals through a receptor complex composed of 2 type I and 2 type II (TGF-beta RII) subunits. We investigated the role of macrophage TGF-ss signaling in fibrosis after AKI in mice with selective monocyte/macrophage TGF-beta RII deletion (macrophage TGF-beta RII(-/-)mice). Four weeks after injury, renal TGF-beta 1 expression and fibrosis were higher in WT mice than macrophage TGF-beta RII(-/-)mice, which had decreased renal macrophages. The in vitro chemotactic response to f-Met-Leu-Phe was comparable between bone marrow-derived monocytes (BMMs) from WT and macrophage TGF-beta RII(-/-)mice, but TGF-beta RII-/-BMMs did not respond to TGF-beta. We then implanted Matrigel plugs suffused with either f-Met-Leu-Phe or TGF-beta 1 into WT or macrophage TGF-beta RII(-/-)mice. After 6 days, f-Met-Leu-Phe induced similar macrophage infiltration into the Matrigel plugs of WT and macrophage TGF-beta RII(-/-)mice, but TGF-beta induced infiltration only in WT mice. We further determined the number of labeled WT or TGF-beta RII-/-BMMs infiltrating into WT kidneys 20 days after ischemic injury. There were more labeled WT BMMs than TGF-beta RII-/-BMMs. Therefore, macrophage TGF-beta RII deletion protects against the development of tubulointerstitial fibrosis following severe ischemic renal injury. Chemoattraction of macrophages to the injured kidney through a TGF-beta/TGF-beta RII axis is a heretofore undescribed mechanism by which TGF-beta can mediate renal fibrosis during progressive renal injury.
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页数：15
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