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EGFR-PLC1 signaling mediates high glucose-induced PKCβ1-Akt activation and collagen I upregulation in mesangial cells

¹Division of Nephrology, McMaster University, Hamilton, Ontario; ²Department of Medicine, University of Melbourne, Fitzroy, Australia; and ³Keenan Research Centre, Li Ka Shing Knowledge Institute and Division of Endocrinology, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada

Submitted 2 February 2009 ; accepted in final form 13 July 2009

Glomerular matrix accumulation is a hallmark of diabetic nephropathy. We have recently shown that epidermal growth factor receptor (EGFR) transactivation mediates high glucose (HG)-induced collagen I upregulation through PI3K-PKCβ1-Akt signaling in mesangial cells (MC). Phospholipase C1 (PLC1) interacts with activated growth factor receptors and activates classic PKC isoforms. We thus studied its role in HG-induced collagen I upregulation in MC. Primary rat MC were treated with HG (30 mM) or mannitol as osmotic control. Protein kinase activation was assessed by Western blotting and collagen I upregulation by Northern blotting. Diabetes was induced in rats by streptozotocin. HG treatment for 1 h led to PLC1 membrane translocation and Y783 phosphorylation, both indicative of its activation. Mannitol was without effect. PLC1 Y783 phosphorylation was also seen in cortex and glomeruli of diabetic rats. HG induced a physical association between EGFR and PLC1 as identified by coimmunoprecipitation. PLC1 activation required EGFR kinase activity since it was prevented by the EGFR inhibitor AG1478 or overexpression of kinase-inactive EGFR (K721A). Phosphoinositide-3-OH kinase inhibition also prevented PLC1 activation. HG-induced Akt S473 phosphorylation, effected by PKCβ1, was inhibited by the PLC inhibitor U73122. [GenBank] PLC1 inhibition or downregulation by small interference RNA also prevented HG-induced collagen I upregulation. Our results indicate that EGFR-PLC1 signaling mediates HG-induced PKCβ1-Akt activation and subsequent collagen I upregulation in MC. Inhibition of EGFR or PLC1 may provide attractive therapeutic targets for the treatment of diabetic nephropathy.

diabetic nephropathy; extracellular matrix; epidermal growth factor receptor