Urea stress is more akin to EGF exposure than to hypertonic stress in renal medullary cells.
Although urea is considered to be a cell stressor even in renal medullary cells perpetually exposed to this solute in vivo by virtue of the renal concentrating mechanism, aspects of urea signaling resemble that of a peptide mitogen. Urea was compared with epidermal growth factor and hypertonic NaCl or hypertonic mannitol using a large-scale expression array-based approach. The expression profile in response to urea stress more closely resembled that of EGF treatment than hypertonic stress, as determined by hierarchical cluster analysis; the effect of urea+NaCl was equidistant from that of either solute applied individually. Among the most highly urea- and hypertonicity-responsive transcripts were genes that had previously been shown to be responsive to these solutes, validating this approach. Increased expression of the activating transcription factor 3 by urea was newly detected via expression array and confirmed via immunoblot analysis. Earlier, we noted an abrogation of tonicity-dependent gene regulation by urea, primarily in a transient transfection-based model (Tian W and Cohen DM. Am J Physiol Renal Physiol 280: F904-F912, 2001). Here we applied K-means cluster analysis to demonstrate that the genes most profoundly up- or downregulated by hypertonic stress were partially restored toward basal levels in the presence of urea pretreatment. These global expression data are consistent with our earlier biochemical studies suggesting that urea affords cytoprotection in this context. In the aggregate, these data strongly support the hypothesis that the urea effect in renal medullary cells resembles that of a peptide mitogen in terms of the adaptive program of gene expression and in terms of cytoprotection from hypertonicity.
Tian
Wei
W
Division of Nephrology, Department of Medicine, Oregon Health and Science University and the Portland Veterans Affairs Medical Center, Portland, Oregon 97201, USA.
Cohen
David M
DM
D051700:Activating Transcription Factor 3; D000818:Animals; D020346:Aquaporins / Q000235:genetics; D002460:Cell Line; D051546:Cyclooxygenase 2; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006982:Hypertonic Solutions; D015151:Immunoblotting; D007527:Isoenzymes / Q000235:genetics; D007679:Kidney Medulla / Q000378:metabolism*; D008353:Mannitol / Q000008:administration & dosage; D051379:Mice; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D012462:Saline Solution, Hypertonic / Q000494:pharmacology; D013312:Stress, Physiological; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection; D014508:Urea / Q000494:pharmacology*
D051700:Activating Transcription Factor 3; D020346:Aquaporins; D051546:Cyclooxygenase 2; D004815:Epidermal Growth Factor; D018840:HSP70 Heat-Shock Proteins; D006982:Hypertonic Solutions; D007527:Isoenzymes; D008353:Mannitol; D011451:Prostaglandin-Endoperoxide Synthases; D012462:Saline Solution, Hypertonic; D014157:Transcription Factors; D014508:Urea; C099678:Hspa4l protein, mouse