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The signaling protein Wnt5a promotes TGF?1-mediated macrophage polarization and kidney fibrosis by inducing the transcriptional regulators Yap/Taz.

ABSTRACT: M2 macrophage polarization is known to underlie kidney fibrosis. We previously reported that most of the members of the Wnt family of signaling proteins are induced in fibrotic kidneys. Dysregulation of the signaling protein Wnt5a is associated with fibrosis, but little is known about the role of Wnt5a in regulating M2 macrophage activation that results in kidney fibrosis. Here, using murine Raw 264.7 cells and bone marrow-derived macrophages, we found that Wnt5a enhanced transforming growth factor ?1 (TGF?1)-induced macrophage M2 polarization as well as expression of the transcriptional regulators Yes-associated protein (Yap)/transcriptional coactivator with PDZ-binding motif (Taz). Verteporfin blockade of Yap/Taz inhibited both Wnt5a- and TGF?1-induced macrophage M2 polarization. In mouse models of kidney fibrosis, shRNA-mediated knockdown of Wnt5a expression diminished kidney fibrosis, macrophage Yap/Taz expression, and M2 polarization. Moreover, genetic ablation of Taz in macrophages attenuated kidney fibrosis and macrophage M2 polarization in mice. Collectively, these results indicate that Wnt5a promotes kidney fibrosis by stimulating Yap/Taz-mediated macrophage M2 polarization.

SUBMITTER: Feng Y

PROVIDER: S-EPMC6302175 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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The signaling protein Wnt5a promotes TGFβ1-mediated macrophage polarization and kidney fibrosis by inducing the transcriptional regulators Yap/Taz.

Feng Ye Y Liang Yan Y Zhu Xingwen X Wang Mingjie M Gui Yuan Y Lu Qingmiao Q Gu Mengru M Xue Xian X Sun Xiaoli X He Weichun W Yang Junwei J Johnson Randy L RL Dai Chunsun C

The Journal of biological chemistry 20181017 50

M2 macrophage polarization is known to underlie kidney fibrosis. We previously reported that most of the members of the Wnt family of signaling proteins are induced in fibrotic kidneys. Dysregulation of the signaling protein Wnt5a is associated with fibrosis, but little is known about the role of Wnt5a in regulating M2 macrophage activation that results in kidney fibrosis. Here, using murine Raw 264.7 cells and bone marrow-derived macrophages, we found that Wnt5a enhanced transforming growth fac ...[more]

PMID: 30333225

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Project description:Rac-GTPases are major regulators of cytoskeletal remodeling and their deregulation contributes to numerous pathologies. Whether or how Rac promotes tubulointerstitial fibrosis and chronic kidney disease (CKD) is currently unknown. We showed that the major profibrotic cytokine, TGF-β1 promoted rapid Rac1-GTP loading in human kidney 2 (HK-2) human renal epithelial cells. A Rac-specific chemical inhibitor, EHT 1864, blocked TGF-β1-induced fibrotic reprogramming in kidney epithelial cells and fibroblasts. Stable Rac1 depletion in HK-2 cells, moreover, eliminated TGF-β1-mediated non-SMAD pathway activation [e.g., Src, epidermal growth factor receptor (EGFR), p53] and subsequent plasminogen activator inhibitor-1 (PAI-1), connective tissue growth factor, fibronectin, and p21 induction. Rac1 and p22phox knockdown abrogated free radical generation by TGF-β1 in HK-2 cells, consistent with the role of Rac1 in NAPD(H). TGF-β1-induced renal epithelial cytostasis was also completely bypassed by Rac1, p22phox, p47phox, and PAI-1 silencing. Rac1b isoform expression was robustly induced in the fibrotic kidneys of mice and humans. Intraperitoneal administration of EHT 1864 in mice dramatically attenuated ureteral unilateral obstruction-driven EGFR, p53, Rac1b, yes-associated protein/transcriptional coactivator with PDZ-binding motif activation/expression, dedifferentiation, cell cycle arrest, and renal fibrogenesis evident in vehicle-treated obstructed kidneys. Thus, the Rac1-directed redox response is critical for TGF-β1-driven epithelial dysfunction orchestrated, in part, via PAI-1 up-regulation. Rac pathway inhibition suppressed renal oxidative stress and maladaptive repair, identifying Rac as a novel therapeutic target against progressive CKD.-Patel, S., Tang, J., Overstreet, J. M., Anorga, S., Lian, F., Arnouk, A., Goldschmeding, R., Higgins, P. J., Samarakoon, R. Rac-GTPase promotes fibrotic TGF-β1 signaling and chronic kidney disease via EGFR, p53, and Hippo/YAP/TAZ pathways.

Dataset Information

The signaling protein Wnt5a promotes TGF?1-mediated macrophage polarization and kidney fibrosis by inducing the transcriptional regulators Yap/Taz.

Publications

The signaling protein Wnt5a promotes TGFβ1-mediated macrophage polarization and kidney fibrosis by inducing the transcriptional regulators Yap/Taz.

Similar Datasets

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