TGFβ instructs mTORC2 to activate PKCβII for increased TWIST1 expression in proximal tubular epithelial cell injury

被引：2
作者：
Das, Falguni [1 ,2 ]
Ghosh-Choudhury, Nandini [3 ]
Maity, Soumya [2 ]
Kasinath, Balakuntalam S. [2 ]
Choudhury, Goutam Ghosh [1 ,2 ,4 ,5 ]
机构：
[1] South Texas Vet Hlth Care Syst, Educ & Clin Ctr, 1VA Res & 4Geriatr Res, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA
[2] UT Hlth San Antonio, Dept Med, San Antonio, TX USA
[3] UT Hlth San Antonio, Dept Pathol, San Antonio, TX USA
[4] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX USA
[5] UT Hlth San Antonio, Dept Med, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA
来源：
FEBS LETTERS | 2023年 / 597卷 / 09期
关键词：
kidney fibrosis; matrix protein expansion; protein kinase C; transforming growth factor-beta; TWIST1; PROTEIN-KINASE-C; TO-MESENCHYMAL TRANSITION; HIGH GLUCOSE; AKT KINASE; RAPAMYCIN COMPLEXES; MAMMALIAN TARGET; OXIDATIVE STRESS; IN-VIVO; SMAD; PATHWAY;
D O I：
10.1002/1873-3468.14599
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：
The plasticity of proximal tubular epithelial cells in response to TGF beta contributes to the expression of TWIST1 to drive renal fibrosis. The mechanism of TWIST1 expression is not known. We show that both PI3 kinase and its target mTORC2 increase TGF beta-induced TWIST1 expression. TGF beta enhances phosphorylation on Ser-660 in the protein kinase C beta II (PKC beta II) hydrophobic motif site. Remarkably, phosphorylation-deficient PKC beta IIS660A, kinase-dead PKC beta II, and PKC beta II knockdown blocked TWIST1 expression by TGF beta. Inhibition of TWIST1 arrested TGF beta-induced tubular cell hypertrophy and the expression of fibronectin, collagen I (alpha 2), and alpha-smooth muscle actin. By contrast, TWIST1 overexpression induced these pathologies. Interestingly, the inhibition of PKC beta II reduced these phenomena, which were countered by the expression of TWIST1. These results provide the first evidence for the involvement of the mTORC2-PKC beta II axis in TWIST1 expression to promote tubular cell pathology.
引用
收藏
页码：1300 / 1316
页数：17
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