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

ABSTRACT: TGF-? signals through a receptor complex composed of 2 type I and 2 type II (TGF-?RII) subunits. We investigated the role of macrophage TGF-? signaling in fibrosis after AKI in mice with selective monocyte/macrophage TGF-?RII deletion (macrophage TGF-?RII-/- mice). Four weeks after injury, renal TGF-?1 expression and fibrosis were higher in WT mice than macrophage TGF-?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-?RII-/- mice, but TGF-?RII-/- BMMs did not respond to TGF-?. We then implanted Matrigel plugs suffused with either f-Met-Leu-Phe or TGF-?1 into WT or macrophage TGF-?RII-/- mice. After 6 days, f-Met-Leu-Phe induced similar macrophage infiltration into the Matrigel plugs of WT and macrophage TGF-?RII-/- mice, but TGF-? induced infiltration only in WT mice. We further determined the number of labeled WT or TGF-?RII-/- BMMs infiltrating into WT kidneys 20 days after ischemic injury. There were more labeled WT BMMs than TGF-?RII-/- BMMs. Therefore, macrophage TGF-?RII deletion protects against the development of tubulointerstitial fibrosis following severe ischemic renal injury. Chemoattraction of macrophages to the injured kidney through a TGF-?/TGF-?RII axis is a heretofore undescribed mechanism by which TGF-? can mediate renal fibrosis during progressive renal injury.

SUBMITTER: Chung S

PROVIDER: S-EPMC6238749 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Chung Sungjin S Overstreet Jessica M JM Li Yan Y Wang Yinqiu Y Niu Aolei A Wang Suwan S Fan Xiaofeng X Sasaki Kensuke K Jin Guan-Nan GN Khodo Stellor Nlandu SN Gewin Leslie L Zhang Ming-Zhi MZ Harris Raymond C RC

JCI insight 20181102 21

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 bo ...[more]

PMID: 30385721

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Project description:BACKGROUND:The prevalence of lupus nephritis (LN) remains high despite various emerging monoclonal antibodies against with targeting systemic lupus erythematosus (SLE). Renal fibrosis is the main feature of late stage LN, and novel therapeutic agents are still needed. We previously reported that microRNA (miR)-150 increases in renal biopsies of American LN patients and that miR-150 agonist promotes fibrosis in cultured kidney cells. Presently, we aim to verify whether locked nucleic acid (LNA)-anti-miR-150 can ameliorate LN in mice and to investigate its corresponding mechanisms. METHODS:We first observed natural history and renal miR-150 expression in female Fcgr2b-/- mice of a spontaneously developed LN model. We then verified miR-150 renal absorption and determined the dose of the suppressed miR-150 by subcutaneous injection of LNA-anti-miR-150 (2 and 4?mg/kg). Thirdly, we investigated the therapeutic effects of LNA-anti-miR-150 (2?mg/kg for 8 weeks) on LN mice and the corresponding mechanisms by studying fibrosis-related genes, cytokines, and kidney resident macrophages. Lastly, we detected the expression of renal miR-150 and the mechanism-associated factors in renal biopsies from new onset untreated LN patients. RESULTS:Fcgr2b-/- mice developed SLE indicated by positive serum autoantibodies at age 19?weeks and LN demonstrated by proteinuria at age 32?weeks. Renal miR-150 was overexpressed in LN mice compared to wild type mice. FAM-labeled LNA-anti-miR-150 was absorbed by both glomeruli and renal tubules. LNA-anti-miR-150 suppressed the elevated renal miR-150 levels in LN mice compared to the scrambled LNA without systemic toxicity. Meanwhile, serum double strand-DNA antibody, proteinuria, and kidney injury were ameliorated. Importantly, the elevated renal pro-fibrotic genes (transforming growth factor-?1, ?-smooth muscle antibody, and fibronectin) and decreased anti-fibrotic gene suppressor of cytokine signal 1 were both reversed. Renal pro-inflammatory cytokines (interferon-?, interleukin-6, and tumor necrosis factor-?) and macrophages were also decreased. In addition, the changes of renal miR-150 and associated proteins shown in LN mice were also seen in human subjects. CONCLUSIONS:LNA-anti-miR-150 may be a promising novel therapeutic agent for LN in addition to the current emerging monoclonal antibodies, and its renal protective mechanism may be mediated by anti-fibrosis and anti-inflammation as well as reduction of the infiltrated kidney resident macrophages.

Dataset Information

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

Publications

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

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