Cells of the renal medulla in vivo are exposed to extraordinarily high concentrations of the potent denaturant urea as a consequence of the renal concentrating mechanism. The molecular mechanism through which these cells respond to and tolerate this harsh environment has implications for the understanding of renal water and urea homeostasis, and for the understanding of and potential enhancement of resistance to metabolic stress in diverse pathophysiological contexts. The applicant has shown that renal epithelial cells uniquely and specifically exhibit a series of signaling responses to exogenous urea that has features of both mitogenic and stress signaling, and which includes activation of effectors of a receptor tyrosine kinase. The overarching hypothesis is that urea favorably regulates the balance between mitogenesis (i.e., cytoprotection) and apoptosis in a renal epithelial cell-specific fashion, and that this effect of urea is achieved indirectly through G-protein-coupled receptor-dependent transactivation of an EGF receptor family member via activation (ectodomain shedding) of heparin-binding epidermal growth factor.
In Aim I, the mechanism through which urea increases D-cyclin expression in renal epithelial cells will be investigated as a correlate of urea-inducible pro-proliferative signaling, through a combination of pharmacological, biochemical, and molecular biological approaches.
In Aim II, the mechanism through which urea protects from the pro-apoptotic effect of hypertonicity in renal epithelial cells will be investigated, with attention to the role of putative cytoprotective signaling intermediates previously shown to be activated by urea.
In Aim III, in light of our newest preliminary data, the role of ectodomain shedding of heparin-binding epidermal growth factor (HB-EGF) will be assessed with respect to the acquisition of the urea-stressed molecular phenotype. In addition, the sufficiency of these and related signaling elements for urea signaling will be examined in models of heterologous expression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052494-06
Application #
6640102
Study Section
Pathology A Study Section (PTHA)
Program Officer
Ketchum, Christian J
Project Start
1997-12-20
Project End
2006-04-30
Budget Start
2003-07-01
Budget End
2004-04-30
Support Year
6
Fiscal Year
2003
Total Cost
$258,965
Indirect Cost
Name
Oregon Health and Science University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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Xu, Hongshi; Tian, Wei; Lindsley, Jessie N et al. (2005) EphA2: expression in the renal medulla and regulation by hypertonicity and urea stress in vitro and in vivo. Am J Physiol Renal Physiol 288:F855-66
Tian, Wei; Salanova, Michele; Xu, Hongshi et al. (2004) Renal expression of osmotically responsive cation channel TRPV4 is restricted to water-impermeant nephron segments. Am J Physiol Renal Physiol 287:F17-24
Xu, Hongshi; Zhao, Hongyu; Tian, Wei et al. (2003) Regulation of a transient receptor potential (TRP) channel by tyrosine phosphorylation. SRC family kinase-dependent tyrosine phosphorylation of TRPV4 on TYR-253 mediates its response to hypotonic stress. J Biol Chem 278:11520-7
Zhao, Hongyu; Tian, Wei; Cohen, David M (2002) Rottlerin inhibits tonicity-dependent expression and action of TonEBP in a PKCdelta-independent fashion. Am J Physiol Renal Physiol 282:F710-7
Tian, Wei; Cohen, David M (2002) Urea stress is more akin to EGF exposure than to hypertonic stress in renal medullary cells. Am J Physiol Renal Physiol 283:F388-98
Komers, Radko; Tian, Wei; Lindsley, Jessie N et al. (2002) Effects of cyclooxygenase-2 (COX-2) inhibition on plasma and renal renin in diabetes. J Lab Clin Med 140:351-7
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Yang, X Y; Zhao, H; Zhang, Z et al. (2001) Urea signaling to ERK phosphorylation in renal medullary cells requires extracellular calcium but not calcium entry. Am J Physiol Renal Physiol 280:F162-71
Tian, W; Bonkovsky, H L; Shibahara, S et al. (2001) Urea and hypertonicity increase expression of heme oxygenase-1 in murine renal medullary cells. Am J Physiol Renal Physiol 281:F983-91

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