Tyrosines-740/751 of PDGFRβ contribute to the activation of Akt/Hif1α/TGFβ nexus to drive high glucose-induced glomerular mesangial cell hypertrophy.
Tyrosines-740/751 of PDGFRβ contribute to the activation of Akt/Hif1α/TGFβ nexus to drive high glucose-induced glomerular mesangial cell hypertrophy.
复制标题
DOI：
10.1016/j.cellsig.2017.09.017
复制
发表时间：
2018-01
影响因子：
4.8
通讯作者：
Choudhury GG
中科院分区：
文献类型：
--
作者：
Das F;Ghosh-Choudhury N;Kasinath BS;Choudhury GG
肾小球系膜细胞肥大是糖尿病肾病的并发症之一。高糖诱导系膜细胞肥大的机制尚不清楚。在这里，我们探讨了血小板衍生生长因子受体-β (PDGFRβ)酪氨酸激酶在驱动高糖诱导的系膜细胞肥大中的作用。我们发现，高葡萄糖刺激PDGFRβ与PI 3激酶的关联，导致后者的酪氨酸磷酸化。高糖诱导的Akt激酶激活也依赖于PDGFRβ及其酪氨酸在740/751位点的磷酸化。抑制PDGFRβ活性，下调其磷酸化缺陷（Y740/751F）突变体的表达，可抑制高糖诱导的系膜细胞肥大。有趣的是，组成型活性Akt的表达逆转了这种抑制作用，表明Akt激酶在PDGFRβ磷酸化的下游发挥了作用。转录因子Hif1α是Akt激酶的靶标。抗Hif1α的sirna抑制高糖诱导的系膜细胞肥大。相反，Hif1α表达增加引起的肥厚与高糖相似。我们发现抑制PDGFRβ和PDGFRβ Y740/751F突变体的表达显著抑制高糖诱导的Hif1α的表达。重要的是，Hif1α的表达抵消了由siPDGFRβ或PDGFRβ Y740/751F突变体诱导的系膜细胞肥大的抑制。最后，我们发现高糖刺激PDGFRβ酪氨酸在740/751残基磷酸化和受体的酪氨酸激酶活性通过Hif1α调节转化生长因子-β (TGFβ)的表达。因此，我们将细胞表面PDGFRβ定义为高糖及其效应物Hif1α和TGFβ诱导糖尿病系膜细胞肥大的主要联系。
Glomerular mesangial cell hypertrophy contributes to the complications of diabetic nephropathy. The mechanism by which high glucose induces mesangial cell hypertrophy is poorly understood. Here we explored the role of the platelet-derived growth factor receptor-β (PDGFRβ) tyrosine kinase in driving the high glucose-induced mesangial cell hypertrophy. We show that high glucose stimulates the association of the PDGFRβ with PI 3 kinase leading to tyrosine phosphorylation of the latter. High glucose-induced Akt kinase activation was also dependent upon PDGFRβ and its tyrosine phosphorylation at 740/751 residues. Inhibition of PDGFRβ activity, its downregulation and expression of its phospho-deficient (Y740/751F) mutant inhibited mesangial cell hypertrophy by high glucose. Interestingly, expression of constitutively active Akt reversed this inhibition, indicating a role of Akt kinase downstream of PDGFRβ phosphorylation in this process. The transcription factor Hif1α is a target of Akt kinase. siRNAs against Hif1α inhibited the high glucose-induced mesangial cell hypertrophy. In contrast, increased expression of Hif1α induced hypertrophy similar to high glucose. We found that inhibition of PDGFRβ and expression of PDGFRβ Y740/751F mutant significantly inhibited the high glucose-induced expression of Hif1α. Importantly, expression of Hif1α countered the inhibition of mesangial cell hypertrophy induced by siPDGFRβ or PDGFRβ Y740/751F mutant. Finally, we show that high glucose-stimulated PDGFRβ tyrosine phosphorylation at 740/751 residues and the tyrosine kinase activity of the receptor regulate the transforming growth factor-β (TGFβ) expression by Hif1α. Thus we define the cell surface PDGFRβ as a major link between high glucose and its effectors Hif1α and TGFβ for induction of diabetic mesangial cell hypertrophy.
登录
查看更多内容
影响因子：
5
作者：
Bhattacharjee, Niloy;Barma, Sujata;Manna, Prasenjit
通讯作者：
Manna, Prasenjit
影响因子：
4.8
作者：
Dey N;Bera A;Das F;Ghosh-Choudhury N;Kasinath BS;Choudhury GG
通讯作者：
Choudhury GG
影响因子：
19.6
作者：
CHOUDHURY, GG;BISWAS, P;ABBOUD, HE
通讯作者：
ABBOUD, HE
影响因子：
19.6
作者：
Bernhardt, WM;Schmitt, R;Eckardt, KU
通讯作者：
Eckardt, KU
影响因子：
9.2
作者：
Alessi, DR;James, SR;Cohen, P
通讯作者：
Cohen, P