Yap/Taz mediates mTORC2-stimulated fibroblast activation and kidney fibrosis

被引：60

作者：

Gui, Yuan ^{[1
]}

Li, Jianzhong ^{[1
]}

Lu, Qingmiao ^{[1
]}

Feng, Ye ^{[1
]}

Wang, Mingjie ^{[1
]}

He, Weichun ^{[1
]}

Yang, Junwei ^{[1
]}

Dai, Chunsun ^{[1
]}

机构：

[1] Nanjing Med Univ, Affiliated Hosp 2, Ctr Kidney Dis, 262 North Zhongshan Rd, Nanjing 210003, Jiangsu, Peoples R China

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2018年 / 293卷 / 42期

基金：

美国国家科学基金会;

关键词：

kidney; Yes-associated protein (YAP); fibroblast; fibrosis; cell signaling; Rictor; EPITHELIAL-MESENCHYMAL TRANSITION; ORGAN SIZE CONTROL; CELL SELF-RENEWAL; HIPPO PATHWAY; MYOFIBROBLAST TRANSITION; RENAL FIBROSIS; PROTEIN YAP; MTOR; GROWTH; DISEASE;

D O I：

10.1074/jbc.RA118.004073

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Our previously published study demonstrated that mammalian target of rapamycin complex 2 (mTORC2) signaling mediates TGF1-induced fibroblast activation. However, the underlying mechanisms for mTORC2 in stimulating fibroblast activation remain poorly understood. Here, we found that TGF1 could stimulate mTORC2 and Yap/Taz activation in NRK-49F cells. Blocking either mTORC2 or Yap/Taz signaling diminished TGF1-induced fibroblast activation. In addition, blockade of mTORC2 could down-regulate the expression of Yap/Taz, connective tissue growth factor (CTGF), and ankyrin repeat domain 1 (ANKRD1). Overexpression of constitutively active Taz (Taz-S89A) could restore fibroblast activation suppressed by PP242, an mTOR kinase inhibitor in NRK-49F cells. In mouse kidneys with unilateral ureter obstructive (UUO) nephropathy, both mTORC2 and Yap/Taz were activated in the interstitial myofibroblasts. Ablation of Rictor in fibroblasts/pericytes or blockade of mTOR signaling with PP242 attenuated Yap/Taz activation and UUO nephropathy in mice. Together, this study uncovers that targeting mTORC2 retards fibroblast activation and kidney fibrosis through suppressing Yap/Taz activation.

引用

页码：16364 / 16375

页数：12

共 47 条

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