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Tyrosines-740/751 of PDGFR? contribute to the activation of Akt/Hif1?/TGF? nexus to drive high glucose-induced glomerular mesangial cell hypertrophy.

ABSTRACT: 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-? (PDGFR?) tyrosine kinase in driving the high glucose-induced mesangial cell hypertrophy. We show that high glucose stimulates the association of the PDGFR? with PI 3 kinase leading to tyrosine phosphorylation of the latter. High glucose-induced Akt kinase activation was also dependent upon PDGFR? and its tyrosine phosphorylation at 740/751 residues. Inhibition of PDGFR? 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 PDGFR? phosphorylation in this process. The transcription factor Hif1? is a target of Akt kinase. siRNAs against Hif1? inhibited the high glucose-induced mesangial cell hypertrophy. In contrast, increased expression of Hif1? induced hypertrophy similar to high glucose. We found that inhibition of PDGFR? and expression of PDGFR? Y740/751F mutant significantly inhibited the high glucose-induced expression of Hif1?. Importantly, expression of Hif1? countered the inhibition of mesangial cell hypertrophy induced by siPDGFR? or PDGFR? Y740/751F mutant. Finally, we show that high glucose-stimulated PDGFR? tyrosine phosphorylation at 740/751 residues and the tyrosine kinase activity of the receptor regulate the transforming growth factor-? (TGF?) expression by Hif1?. Thus we define the cell surface PDGFR? as a major link between high glucose and its effectors Hif1? and TGF? for induction of diabetic mesangial cell hypertrophy.

SUBMITTER: Das F

PROVIDER: S-EPMC5889140 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Tyrosines-740/751 of PDGFRβ contribute to the activation of Akt/Hif1α/TGFβ nexus to drive high glucose-induced glomerular mesangial cell hypertrophy.

Das Falguni F Ghosh-Choudhury Nandini N Kasinath Balakuntalam S BS Choudhury Goutam Ghosh GG

Cellular signalling 20170923

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 ...[more]

PMID: 28951244

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Project description:Interaction of transforming growth factor-β (TGFβ)-induced canonical signaling with the noncanonical kinase cascades regulates glomerular hypertrophy and matrix protein deposition, which are early features of glomerulosclerosis. However, the specific target downstream of the TGFβ receptor involved in the noncanonical signaling is unknown. Here, we show that TGFβ increased the catalytic loop phosphorylation of platelet-derived growth factor receptor β (PDGFRβ), a receptor tyrosine kinase expressed abundantly in glomerular mesangial cells. TGFβ increased phosphorylation of the PI 3-kinase-interacting Tyr-751 residue of PDGFRβ, thus activating Akt. Inhibition of PDGFRβ using a pharmacological inhibitor and siRNAs blocked TGFβ-stimulated phosphorylation of proline-rich Akt substrate of 40 kDa (PRAS40), an intrinsic inhibitory component of mTORC1, and prevented activation of mTORC1 in the absence of any effect on Smad 2/3 phosphorylation. Expression of constitutively active myristoylated Akt reversed the siPDGFRβ-mediated inhibition of mTORC1 activity; however, co-expression of the phospho-deficient mutant of PRAS40 inhibited the effect of myristoylated Akt, suggesting a definitive role of PRAS40 phosphorylation in mTORC1 activation downstream of PDGFRβ in mesangial cells. Additionally, we demonstrate that PDGFRβ-initiated phosphorylation of PRAS40 is required for TGFβ-induced mesangial cell hypertrophy and fibronectin and collagen I (α2) production. Increased activating phosphorylation of PDGFRβ is also associated with enhanced TGFβ expression and mTORC1 activation in the kidney cortex and glomeruli of diabetic mice and rats, respectively. Thus, pursuing TGFβ noncanonical signaling, we identified how TGFβ receptor I achieves mTORC1 activation through PDGFRβ-mediated Akt/PRAS40 phosphorylation to spur mesangial cell hypertrophy and matrix protein accumulation. These findings provide support for targeting PDGFRβ in TGFβ-driven renal fibrosis.

Dataset Information

Tyrosines-740/751 of PDGFR? contribute to the activation of Akt/Hif1?/TGF? nexus to drive high glucose-induced glomerular mesangial cell hypertrophy.

Publications

Tyrosines-740/751 of PDGFRβ contribute to the activation of Akt/Hif1α/TGFβ nexus to drive high glucose-induced glomerular mesangial cell hypertrophy.

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