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1 Division of Nephrology and Hypertension, Oregon Health & Science University, Portland, OR, USA; Portland Veterans Affairs Medical Center, Portland, OR, USA
2 Department of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO, USA
3 Department of Medicine, Section of Nephrology, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA
4 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: cohend{at}ohsu.edu.
EphA2, a member of the large family of Eph receptor tyrosine kinases, is highly expressed in epithelial tissue and has been implicated in cell-cell and cell-matrix interactions, as well as cell growth and survival. Expression of EphA2 mRNA and protein was markedly upregulated by both hypertonic stress and by elevated urea concentrations in cells derived from the murine inner medullary collecting duct (mIMCD3). This upregulation likely required transactivation of the EGF receptor tyrosine kinase and metalloproteinase-dependent ectodomain cleavage of an EGF receptor ligand, based upon pharmacological inhibitor studies. A human EphA2 promoter fragment spanning nucleotides -4030 to +21 relative to the putative EphA2 transcriptional start site was responsive to tonicity but insensitive to urea. A promoter fragment spanning -1890 to +128 recapitulated both tonicity- and urea-dependent upregulation of expression, consistent with transcriptional activation. Neither the bona fide p53 response element at ~ -1.5 kB, nor a pair of putative TonE elements at ~ -3 kB conferred the tonicity-responsiveness. EphA2 mRNA and protein were expressed at low levels in rat renal cortex, but at high levels in the collecting ducts of the renal medulla and papilla. Water deprivation in rats increased EphA2 expression in renal papilla, whereas dietary supplementation with 20% urea increased EphA2 expression in outer medulla. These data indicate that transcription and expression of the EphA2 receptor tyrosine kinase is regulated by tonicity and urea in vitro and suggest that this phenomenon is also operative in vivo. Renal medullary EphA2 expression may represent an adaptive response to medullary hypertonicity or urea exposure.
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