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Albumin Activates ERK Via EGF Receptor in Human Renal Epithelial Cells

Heather Reich^*, David Tritchler, Andrew M. Herzenberg, Zamaneh Kassiri, Xiaohua Zhou^||, Wei Gao^|| and James W. Scholey^*

^* Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada; Division of Epidemiology and Statistics, Ontario Cancer Institute, and University of Toronto, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada; and Experimental Therapeutics, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada; ^|| Department of Medicine, University of Toronto, Toronto, Ontario, Canada

Address correspondence to: Dr Heather Reich, University of Toronto, Medical Sciences Building, Clinical Science Division, Room 7326, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada. Phone: 416-978-6870; Fax: 416-978-8765; h.reich{at}utoronto.ca

Received for publication March 23, 2004. Accepted for publication February 25, 2005.

Emerging clinical and experimental evidence strongly implicates proteinuria in the progression of kidney disease. One pathway involves the activation of NFB by albumin, and it has been demonstrated that the activation of NFB induced by albumin is dependent on mitogen-activated protein kinase ERK1/ERK2. To study the effect of albumin on gene expression, primary human renal tubular cells were exposed in vitro to albumin (1%) for 6 h, and gene expression profiling was performed with the human oligonucleotide microarray, U133A Affymetrix Gene Chip. In all, 223 genes were differentially regulated by albumin, including marked upregulation of the EGF receptor (EGFR) and IL-8. Accordingly, the authors sought to delineate the signaling pathway linking albumin to the EGFR and activation of ERK1/ERK2. It was found that albumin led to a dose- and time-dependent activation of ERK1/ERK2. Treatment with albumin led to EGFR phosphorylation, but the activation of ERK1/ERK2 was prevented by pretreatment of the cells with AG-1478, the EGFR kinase inhibitor, at a dose that inhibited EGF-induced ERK1/ERK2 activation. Exogenously administered reactive oxygen species (ROS) were found to activate ERK1/ERK2 via the EGFR and src tyrosine kinase activity and pretreatment of cells with the antioxidant N-acetylcysteine (NAC) and the NADPH oxidase inhibitor DPI abrogated albumin-induced activation of ERK1/ERK2. The src tyrosine kinase inhibitor, PP2, also inhibited the albumin-induced activation of ERK1/ERK2. Finally, pretreatment with AG-1478, the MEK inhibitor UO126, and NAC prevented the albumin-induced increase in IL-8 expression. The authors conclude that the EGF receptor plays a central role in the signaling pathway that links albumin to the activation of ERK1/ERK2 and increased expression of IL-8. Gene profiling studies suggest that there may be a positive feedback loop through the EGFR that amplifies the response of the proximal tubule cell to albumin. Taken together, these results suggest that the EGFR may be an important treatment target for kidney disease associated with proteinuria.

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