Journal
JCI INSIGHT
Volume 3, Issue 21, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.123563
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Funding
- NIH, National Institute of Diabetes and Digestive and Kidney Diseases [DK051265, DK062794, DK095785, DK108968]
- Vanderbilt O'Brien Kidney Center [DK114809]
- U.S. Department of Veterans Affairs
- American Heart Association Postdoctoral Fellowship Award
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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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