Das Falguni, Ghosh-Choudhury Nandini, Maity Soumya, Kasinath Balakuntalam S, Ghosh Choudhury Goutam
1VA Research and 4Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, 7400 Merton Minter Boulevard, San Antonio, TX, 78229, USA.
Department of Medicine, UT Health San Antonio, TX, USA.
FEBS Lett. 2023 May;597(9):1300-1316. doi: 10.1002/1873-3468.14599. Epub 2023 Feb 19.
The plasticity of proximal tubular epithelial cells in response to TGFβ 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 TGFβ-induced TWIST1 expression. TGFβ enhances phosphorylation on Ser-660 in the protein kinase C βII (PKCβII) hydrophobic motif site. Remarkably, phosphorylation-deficient PKCβIIS660A, kinase-dead PKCβII, and PKCβII knockdown blocked TWIST1 expression by TGFβ. Inhibition of TWIST1 arrested TGFβ-induced tubular cell hypertrophy and the expression of fibronectin, collagen I (α2), and α-smooth muscle actin. By contrast, TWIST1 overexpression induced these pathologies. Interestingly, the inhibition of PKCβII reduced these phenomena, which were countered by the expression of TWIST1. These results provide the first evidence for the involvement of the mTORC2-PKCβII axis in TWIST1 expression to promote tubular cell pathology.
近端肾小管上皮细胞对转化生长因子β（TGFβ）的可塑性反应有助于TWIST1的表达，从而驱动肾纤维化。TWIST1表达的机制尚不清楚。我们发现，磷脂酰肌醇-3激酶（PI3激酶）及其靶点雷帕霉素靶蛋白复合物2（mTORC2）均能增加TGFβ诱导的TWIST1表达。TGFβ增强蛋白激酶CβII（PKCβII）疏水基序位点丝氨酸660的磷酸化。值得注意的是，磷酸化缺陷型PKCβIIS660A、激酶失活型PKCβII和PKCβII基因敲低均能阻断TGFβ诱导的TWIST1表达。抑制TWIST1可阻止TGFβ诱导的肾小管细胞肥大以及纤连蛋白、I型胶原（α2）和α平滑肌肌动蛋白的表达。相反，TWIST1过表达会诱导这些病理变化。有趣的是，抑制PKCβII可减少这些现象，而TWIST1的表达可抵消这种抑制作用。这些结果首次证明了mTORC2-PKCβII轴参与TWIST1表达以促进肾小管细胞病理变化。
