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1 Portland Veterans Affairs Medical Center, Portland, OR, USA
2 Division of Nephrology and Hypertension, Oregon Health & Science University, Portland, OR, USA
3 Division of Nephrology and Hypertension, Oregon Health & Science University, Portland, OR, USA; Portland Veterans Affairs Medical Center, Portland, OR, USA
* To whom correspondence should be addressed. E-mail: cohend{at}ohsu.edu.
Hypertonic stress increases expression of COX-2 in renal medullary epithelial cells and in renal medullary interstitial cells. Because hypertonic COX-2 expression is, in part, sensitive to inhibition of the ERK mitogen activated protein kinase-an effector of activated receptor tyrosine kinases such as the EGF receptor, we investigated a role for this receptor in signaling to COX-2 expression. Consistent with the data of others, and with our prior microarray based data, hypertonic stress increased COX-2 expression at the mRNA and protein levels at 6 and 24 h of hypertonic treatment. Two potent, highly specific inhibitors of the EGF receptor kinase, AG1478 and PD153035, abrogated this effect. These inhibitors also blocked the ability of hypertonic stress to increase prostaglandin E2 release; in addition, they partially blocked tonicity-dependent phosphorylation of ERK but not of the related MAPKs, JNK or p38. Consistent with these data, pharmacological inhibition of ERK activation partially blocked tonicity-dependent COX-2 expression. Hypertonic induction of COX-2 was likely transcriptionally mediated as NaCl stress increased reporter gene activity in mIMCD3 cells stably transfected with an expression plasmid encoding luciferase under control of the human COX-2 promoter; this effect was also sensitive to inhibition of the EGF receptor kinase. Metalloproteinase action is required for transactivation of the EGF receptor and pharmacological inhibition of metalloproteinase function blocked tonicity-inducible COX-2 expression. Furthermore, the effect of hypertonicity upon COX-2 expression was also evident in the EGF-responsive MDCK and 3T3 cell lines, but was virtually absent from the EGF-unresponsive (and EGF receptor-null) Chinese hamster-derived CHO cell line. Taken together, these data strongly suggest that hypertonicitydependent COX-2 expression in renal medullary cells requires transactivation of the EGF receptor, and that this phenomenon may require ectodomain cleavage of an EGF receptor ligand.
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