Deletion of STAT3 from Foxd1 cell population protects mice from kidney fibrosis by inhibiting pericytes trans-differentiation and migration

被引:28
作者
Ajay, Amrendra K. [1 ,2 ]
Zhao, Li [1 ,2 ,3 ]
Vig, Shruti [1 ,2 ]
Fujiwara, Mai [2 ,4 ]
Thakurela, Sudhir [5 ]
Jadhav, Shreyas [1 ,2 ]
Cho, Andrew [1 ,2 ]
I-Jen Chiu [1 ,2 ]
Ding, Yan [1 ,2 ]
Ramachandran, Krithika [1 ,2 ]
Mithal, Arushi [1 ,2 ]
Bhatt, Aanal [1 ,2 ]
Chaluvadi, Pratyusha [1 ,2 ]
Gupta, Manoj K. [2 ,6 ]
Shah, Sujal, I [2 ,7 ]
Sabbisetti, Venkata S. [1 ,2 ]
Waaga-Gasser, Ana Maria [1 ,2 ]
Frank, David A. [8 ,9 ]
Murugaiyan, Gopal [2 ,4 ]
Bonventre, Joseph, V [1 ,2 ]
Li-Li Hsiao [1 ,2 ]
机构
[1] Brigham & Womens Hosp, Dept Med, Div Renal Med, 75 Francis St, Boston, MA 02115 USA
[2] Harvard Med Sch, Boston, MA 02115 USA
[3] Beijing Univ Chinese Med, Dongzhimen Hosp, Div Renal Med, Beijing 100700, Peoples R China
[4] Brigham & Womens Hosp, Ann Romney Ctr Neurol Dis, Dept Neurol, 75 Francis St, Boston, MA 02115 USA
[5] Harvard Univ, Broad Inst MIT & Harvard, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA
[6] Joslin Diabet Ctr, Sect Islet Cell Biol & Regenerat Med, Boston, MA 02215 USA
[7] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA
[8] Dana Farber Canc Res Inst, Dept Med Oncol, Boston, MA 02215 USA
[9] Harvard Med Sch, Dept Med, Brigham & Womens Hosp, Boston, MA 02115 USA
来源
CELL REPORTS | 2022年 / 38卷 / 10期
基金
美国国家科学基金会;
关键词
GROWTH-FACTOR; TGF-BETA; SIGNAL TRANSDUCER; GENE-EXPRESSION; CARCINOMA CELLS; ACTIVATION; DISEASE; ORIGIN; PATHWAY; INJURY;
D O I
10.1016/j.celrep.2022.110473
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Signal transduction and activator of transcription 3 (STAT3) is a key transcription factor implicated in the pathogenesis of kidney fibrosis. Although Stat3 deletion in tubular epithelial cells is known to protect mice from fibrosis, vFoxd1 cells remains unclear. Using Foxd1-mediated Stat3 knockout mice, CRISPR, and inhibitors of STAT3, we investigate its function. STAT3 is phosphorylated in tubular epithelial cells in acute kidney injury, whereas it is expanded to interstitial cells in fibrosis in mice and humans. Foxd1-mediated deletion of Stat3 protects mice from folic -acid-and aristolochic-acid-induced kidney fibrosis. Mechanistically, STAT3 upregulates the inflammation and differentiates pericytes into myofibroblasts. STAT3 activation increases migration and profibrotic signaling in genome-edited, pericyte-like cells. Conversely, blocking Stat3 inhibits detachment, migration, and profibrotic signaling. Furthermore, STAT3 binds to the Collagen1a1 promoter in mouse kidneys and cells. Together, our study identifies a previously unknown function of STAT3 that promotes kidney fibrosis and has therapeutic value in fibrosis.
引用
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页数:23
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