Cadmium is an important industrial and environmental toxin causing well known human health problems. Most humans are exposed to cadmium at low concentrations over extended periods, and the most significant target of such exposure are kidney (renal) tubular epithelial cells (RTEs). Cadmium exposure alters cytoskeletal regulation in exposed RTEs, and limited data indicate that cadmium induces changes in expression or regulation of proteins including hsp27, a stress response protein known to regulate actin filament assembly. Few studies have specifically examined hsp27 regulation or function during extended low level cadmium exposure and neither the precise manner nor the significance of altered hsp27 expression and regulation in RTEs are well understood. In preliminary studies, we find that low doses of cadmium over periods of several days induces alteration in actin organization and observe concomitant increases in expression of nonphosphorylated hsp27. We also provide the first direct analysis of actin distribution kinetics in living, cadmium treated RTEs, revealing that cadmium induces dramatic alterations in the dynamic regulation of actin filament structures not apparent from static images. Because changes in hsp27 function observed in our studies have been correlated with reduced actin filament assembly or stabilization in other systems, we hypothesize that chronic cadmium exposure can alter actin filament stabilization and causes consequent changes in actin organization in RTEs as a direct consequence of increased hsp27 expression and cytoskeletal association. Additionally, although hsp27 has been shown to protect individual cells against injury, numerous studies make clear that altered hsp27 expression and phosphorylation accompany or induce changes in cell differentiation. Changes in cell structure and function as a consequence of altered actin regulation are also well documented. Thus, we also hypothesize that increased hsp27 expression in RTEs chronically exposed to cadmium, although enhancing individual cell survival, alters cell structure and behavior leading to eventual loss of tissue and organ function. Experiments proposed here will test these hypothesis and will define the role of hsp27 in chronic cadmium induced injury to renal tubule epithelial cells. These studies are also expected to provide new data on the molecular mechanisms of cadmium induced cellular injury and have the potential to suggest novel approaches to the treatment or prevention of renal injury induced by cadmium and similar toxicants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES011196-05
Application #
6771163
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Balshaw, David M
Project Start
2001-07-18
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2006-06-30
Support Year
5
Fiscal Year
2004
Total Cost
$220,200
Indirect Cost
Name
Washington State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164
Tran, Chinh N; Lundy, Steven K; White, Peter T et al. (2007) Molecular interactions between T cells and fibroblast-like synoviocytes: role of membrane tumor necrosis factor-alpha on cytokine-activated T cells. Am J Pathol 171:1588-98
Bryantsev, A L; Chechenova, M B; Shelden, E A (2007) Recruitment of phosphorylated small heat shock protein Hsp27 to nuclear speckles without stress. Exp Cell Res 313:195-209
Mao, L; Shelden, E A (2006) Developmentally regulated gene expression of the small heat shock protein Hsp27 in zebrafish embryos. Gene Expr Patterns 6:127-33
Mao, Li; Bryantsev, Anton L; Chechenova, Maria B et al. (2005) Cloning, characterization, and heat stress-induced redistribution of a protein homologous to human hsp27 in the zebrafish Danio rerio. Exp Cell Res 306:230-41
Hirano, Sahoko; Sun, Xiankui; DeGuzman, Cheryl A et al. (2005) p38 MAPK/HSP25 signaling mediates cadmium-induced contraction of mesangial cells and renal glomeruli. Am J Physiol Renal Physiol 288:F1133-43
Sun, Xiankui; Fontaine, Jean-Marc; Rest, Joshua S et al. (2004) Interaction of human HSP22 (HSPB8) with other small heat shock proteins. J Biol Chem 279:2394-402
Hirano, Sahoko; Shelden, Eric A; Gilmont, Robert R (2004) HSP27 regulates fibroblast adhesion, motility, and matrix contraction. Cell Stress Chaperones 9:29-37
Rajagopalan, Sanjay; Somers, Emily C; Brook, Robert D et al. (2004) Endothelial cell apoptosis in systemic lupus erythematosus: a common pathway for abnormal vascular function and thrombosis propensity. Blood 103:3677-83
Bonham, Rita T; Fine, Michael R; Pollock, Fiona M et al. (2003) Hsp27, Hsp70, and metallothionein in MDCK and LLC-PK1 renal epithelial cells: effects of prolonged exposure to cadmium. Toxicol Appl Pharmacol 191:63-73
Kaplan, Mariana J; Lewis, Emily E; Shelden, Eric A et al. (2002) The apoptotic ligands TRAIL, TWEAK, and Fas ligand mediate monocyte death induced by autologous lupus T cells. J Immunol 169:6020-9

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