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PKC-β1 Mediates Glucose-Induced Akt Activation and TGF-β1 Upregulation in Mesangial Cells

Dongcheng Wu^*, Fangfang Peng^*, Baifang Zhang^*, Alistair J. Ingram^*, Darren J. Kelly, Richard E. Gilbert, Bo Gao^* and Joan C. Krepinsky^*

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

Correspondence: Dr. Joan C. Krepinsky, St. Joseph's Hospital, 50 Charlton Avenue E, Room T3311, Hamilton, ON, L8N 4A6, Canada. Phone: 905-522-1155 ext. 34991; Fax: 905-540-6589; E-mail: krepinj{at}mcmaster.ca

Received for publication April 30, 2008. Accepted for publication October 7, 2008.

Accumulation of glomerular matrix is a hallmark of diabetic nephropathy. The serine/threonine kinase Akt mediates glucose-induced upregulation of collagen I in mesangial cells through transactivation of the EGF receptor (EGFR). In addition, in renal tubular cells, glucose-induced secretion of TGF-β requires phosphoinositide-3-OH kinase, suggesting a possible role for Akt in the modulation of TGF-β expression, but the mechanisms of Akt activation and its involvement in TGF-β regulation are unknown. Here, in primary mesangial cells, high glucose induced AktS473 phosphorylation, which correlates with its activation, in a protein kinase C β (PKC-β)-dependent manner. Glucose led to PKC-β1 membrane translocation and association with Akt, and PKC-β1 immunoprecipitated from glucose-treated cells phosphorylated recombinant Akt on S473. PKC is known to mediate glucose-induced TGF-β1 upregulation through the transcription factor AP-1; here, inhibitors of phosphoinositide-3-OH kinase, PKC-β and Akt, and dominant-negative Akt all prevented glucose-induced activation of AP-1 and upregulation of TGF-β1. Finally, pharmacologic and dominant negative inhibition of EGFR blocked glucose-induced activation of PKC-β1, phosphorylation of AktS473, activation of AP-1, and upregulation of TGF-β1. In vivo, the PKC-β inhibitor ruboxistaurin prevented Akt activation in the renal cortex of diabetic rats. In conclusion, PKC-β1 is an Akt S473 kinase in glucose-treated mesangial cells, and TGF-β1 transcriptional upregulation requires EGFR/PKC-β1/Akt signaling. New therapeutic approaches for diabetic nephropathy may result from targeting components of this pathway, particularly the initial EGFR transactivation.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673