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Research Article
Regulation of profibrotic responses by ADAM17 activation in high glucose requires its C-terminus and FAK
Renzhong Li, Tony Wang, Khyati Walia, Bo Gao, Joan C. Krepinsky
Journal of Cell Science 2018 131: jcs208629 doi: 10.1242/jcs.208629 Published 20 February 2018
Renzhong Li
Division of Nephrology, McMaster University, Hamilton, Canada, L8N 4A6
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Tony Wang
Division of Nephrology, McMaster University, Hamilton, Canada, L8N 4A6
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  • ORCID record for Tony Wang
Khyati Walia
Division of Nephrology, McMaster University, Hamilton, Canada, L8N 4A6
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Bo Gao
Division of Nephrology, McMaster University, Hamilton, Canada, L8N 4A6
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Joan C. Krepinsky
Division of Nephrology, McMaster University, Hamilton, Canada, L8N 4A6
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  • For correspondence: krepinj@mcmaster.ca
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ABSTRACT

Glomerular matrix accumulation is the hallmark of diabetic nephropathy. The metalloprotease ADAM17 mediates high glucose (HG)-induced matrix production by kidney mesangial cells through release of ligands for the epidermal growth factor receptor. Here, we study the mechanism by which HG activates ADAM17. We find that the C-terminus is essential for ADAM17 activation and the profibrotic response to HG. In the C-terminus, Src-mediated Y702 phosphorylation and PI3K–MEK–Erk-mediated T735 phosphorylation are crucial for ADAM17 activation, both are also required for the HG-induced increase in cell surface mature ADAM17. The non-receptor tyrosine kinase FAK is a central mediator of these processes. These data not only support a crucial role for the C-terminus in ADAM17 activation and downstream profibrotic responses to HG, but also highlight FAK as a potential alternative therapeutic target for diabetic nephropathy.

Footnotes

  • Competing interests

    The authors declare no competing or financial interests.

  • Author contributions

    Conceptualization: J.C.K.; Methodology: R.L.; Formal analysis: J.C.K.; Data curation: R.L., T.W., K.W., B.G.; Writing - original draft: J.C.K.; Writing - review & editing: J.C.K.; Supervision: J.C.K.; Project administration: J.C.K.

  • Funding

    This work was supported by the Institute of Nutrition, Metabolism and Diabetes of the Canadian Institutes of Health Research (CIHR) (MOP119308 to J.C.K.).

  • Supplementary information

    Supplementary information available online at http://jcs.biologists.org/lookup/doi/10.1242/jcs.208629.supplemental

  • Received July 17, 2017.
  • Accepted December 28, 2017.
  • © 2018. Published by The Company of Biologists Ltd
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Keywords

  • ADAM17
  • Glucose
  • Fibrosis
  • Trafficking
  • Signaling

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Research Article
Regulation of profibrotic responses by ADAM17 activation in high glucose requires its C-terminus and FAK
Renzhong Li, Tony Wang, Khyati Walia, Bo Gao, Joan C. Krepinsky
Journal of Cell Science 2018 131: jcs208629 doi: 10.1242/jcs.208629 Published 20 February 2018
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Research Article
Regulation of profibrotic responses by ADAM17 activation in high glucose requires its C-terminus and FAK
Renzhong Li, Tony Wang, Khyati Walia, Bo Gao, Joan C. Krepinsky
Journal of Cell Science 2018 131: jcs208629 doi: 10.1242/jcs.208629 Published 20 February 2018

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