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By analyzing the kidney tissues from patients and animal models with kidney fibrosis, we found a large induction of PP2Ac\u03b1 in macrophages. We then generated a mouse model with inducible macrophage ablation of PP2Ac\u03b1. The knockouts developed less renal fibrosis, macrophage accumulation, or tubular cell death after unilateral ureter obstruction or ischemic reperfusion injury compared to control littermates. In cultured macrophages, PP2Ac\u03b1 deficiency resulted in decreased cell motility by inhibiting Rap1 activity. Moreover, co-culture of PP2Ac\u03b1<jats:sup>\u2212\/\u2212<\/jats:sup>macrophages with tubular cells resulted in less tubular cell death attributed to downregulated Stat6-mediated tumor necrosis factor \u03b1 (TNF\u03b1) production in macrophages. Together, this study demonstrates that PP2Ac\u03b1 promotes macrophage accumulation and activation, hence accelerates tubular cell death and kidney fibrosis through regulating Rap1 activation and TNF\u03b1 production.<\/jats:p>","DOI":"10.1038\/s41418-021-00780-5","type":"journal-article","created":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T11:58:59Z","timestamp":1620043139000},"page":"2728-2744","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["PP2Ac\u03b1 promotes macrophage accumulation and activation to exacerbate tubular cell death and kidney fibrosis through activating Rap1 and TNF\u03b1 production"],"prefix":"10.1038","volume":"28","author":[{"given":"Yan","family":"Liang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingmiao","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengru","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengzhu","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7616-2469","authenticated-orcid":false,"given":"Chunsun","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,1]]},"reference":[{"key":"780_CR1","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1016\/S0140-6736(13)60687-X","volume":"382","author":"V Jha","year":"2013","unstructured":"Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, et al. 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