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.

肾小球系膜细胞肥大导致糖尿病性肾病的并发症。人们对高葡萄糖诱导肾小球膜细胞肥大的机制了解甚少。在这里，我们探讨了血小板源性生长因子受体-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。我们显示高葡萄糖刺激PDGFRβ与PI 3激酶的结合，导致后者的酪氨酸磷酸化。高葡萄糖诱导的Akt激酶活化还取决于PDGFRβ及其在740/751残基处的酪氨酸磷酸化。PDGFRβ活性的抑制，它的下调和其磷酸缺乏的（Y740 / 751F）突变体的表达抑制了高葡萄糖对系膜细胞肥大的影响。有趣的是，组成型活性Akt的表达逆转了这种抑制作用，提示在此过程中Akt激酶在PDGFRβ磷酸化下游的作用。转录因子Hif1α是Akt激酶的靶标。针对Hif1α的siRNA抑制了高糖诱导的系膜细胞肥大。相反，Hif1α的表达增加诱导了与高葡萄糖相似的肥大。我们发现PDGFRβ的抑制和PDGFRβY740 / 751F突变体的表达显着抑制了高糖诱导的Hif1α的表达。重要的是，Hif1α的表达抵消了siPDGFRβ或PDGFRβY740 / 751F突变体诱导的系膜细胞肥大的抑制作用。最后，我们显示高葡萄糖刺激的740/751残基处的PDGFRβ酪氨酸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。