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J. Biol. Chem., Vol. 280, Issue 22, 21036-21042, June 3, 2005

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p38 Kinase-mediated Transactivation of the Epidermal Growth Factor Receptor Is Required for Dedifferentiation of Renal Epithelial Cells after Oxidant Injury^*

Shougang Zhuang, Yan Yan, Jiahuai Han¶, and Rick G. Schnellmann||

From the Departments of Pharmaceutical Sciences and Surgery, Medical University of South Carolina, Charleston, South Carolina 29425 and ^¶Department of Immunology, The Scripps Research Institute, La Jolla, California 92037

Renal proximal tubular cell (RPTC) dedifferentiation is thought to be a prerequisite for regenerative proliferation and migration after renal injury. However, the specific mediators and the mechanisms that regulate RPTC dedifferentiation have not been elucidated. Because epidermal growth factor (EGF) receptor activity is required for recovery from acute renal failure, we examined the role of the EGF receptor in dedifferentiation and the mechanisms of EGF receptor transactivation in primary cultures of RPTCs after oxidant injury. Exposure of confluent RPTCs to H₂O₂ resulted in 40% cell death, and surviving RPTCs acquired a dedifferentiated phenotype (e.g. elongated morphology and vimetin expression). The EGF receptor, p38, Src, and MKK3 were activated after oxidant injury and inhibition of the EGF receptor or p38 with specific inhibitors (AG1478 and SB203580, respectively) blocked RPTC dedifferentiation. Treatment with SB203580 or adenoviral overexpression of dominant negative p38 or its upstream activator, MKK3, inhibited EGF receptor phosphorylation induced by oxidant injury, whereas AG1478 had no effect on p38 phosphorylation. Inhibition of Src with 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]-pyrimidine (PP1) blocked MKK3 and p38 activation, and inhibition of MKK3 blocked p38 activation. In addition, inactivation of Src, MKK3, p38, or the EGF receptor blocked tyrosine phosphorylation of -catenin, a key signaling intermediate that is involved in the epithelial-mesenchymal transition and vimentin expression. These results reveal that p38 mediates EGF receptor activation after oxidant injury; that Src activates MMK3, which, in turn, activates p38; and that the EGF receptor signaling pathway plays a critical role in RPTC dedifferentiation.

Received for publication, November 25, 2004 , and in revised form, March 23, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Pharmaceutical Sciences, Medical University of South Carolina, 280 Calhoun St., POB 250140, Charleston, SC 29425. Tel.: 843-792-3754; Fax: 843-792-2620; E-mail: schnell{at}musc.edu.

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