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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