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

• Published in: JCI insight 2018-11, Vol.3 (21)
• Main Authors: Chung, Sungjin, Overstreet, Jessica M, Li, Yan, Wang, Yinqiu, Niu, Aolei, Wang, Suwan, Fan, Xiaofeng, Sasaki, Kensuke, Jin, Guan-Nan, Khodo, Stellor Nlandu, Gewin, Leslie, Zhang, Ming-Zhi, Harris, Raymond C
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - complications; Acute Kidney Injury - pathology; Animals; Bone Marrow Cells - cytology; Chemotactic Factors - metabolism; Chemotactic Factors - physiology; Fibrosis - etiology; Fibrosis - metabolism; Kidney - metabolism; Kidney - pathology; Macrophages - metabolism; Male; Mice; Mice, Transgenic - metabolism; Monocytes - metabolism; N-Formylmethionine Leucyl-Phenylalanine - metabolism; Receptor, Transforming Growth Factor-beta Type II - metabolism; Receptors, Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta1 - metabolism
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.123563

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.