Abstract
TGF-β signals through a receptor complex composed of 2 type I and 2 type II (TGF-βRII) subunits. We investigated the role of macrophage TGF-β signaling in fibrosis after AKI in mice with selective monocyte/macrophage TGF-βRII deletion (macrophage TGF-βRII–/– mice). Four weeks after injury, renal TGF-β1 expression and fibrosis were higher in WT mice than macrophage TGF-βRII–/– 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-βRII–/– mice, but TGF-βRII–/– BMMs did not respond to TGF-β. We then implanted Matrigel plugs suffused with either f-Met-Leu-Phe or TGF-β1 into WT or macrophage TGF-βRII–/– mice. After 6 days, f-Met-Leu-Phe induced similar macrophage infiltration into the Matrigel plugs of WT and macrophage TGF-βRII–/– mice, but TGF-β induced infiltration only in WT mice. We further determined the number of labeled WT or TGF-βRII–/– BMMs infiltrating into WT kidneys 20 days after ischemic injury. There were more labeled WT BMMs than TGF-βRII–/– BMMs. Therefore, macrophage TGF-βRII deletion protects against the development of tubulointerstitial fibrosis following severe ischemic renal injury. Chemoattraction of macrophages to the injured kidney through a TGF-β/TGF-βRII axis is a heretofore undescribed mechanism by which TGF-β can mediate renal fibrosis during progressive renal injury.
Authors
Sungjin Chung, Jessica M. Overstreet, Yan Li, Yinqiu Wang, Aolei Niu, Suwan Wang, Xiaofeng Fan, Kensuke Sasaki, Guan-Nan Jin, Stellor Nlandu Khodo, Leslie Gewin, Ming-Zhi Zhang, Raymond C. Harris
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