ToxSci Advance Access originally published online on April 14, 2004
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Toxicological Sciences 80, 170-182 (2004)
Toxicological Sciences vol. 80 no. 1 © Society of Toxicology 2004; all rights reserved.
Disruption of Cadherin/Catenin Expression, Localization, and Interactions During HgCl2-Induced Nephrotoxicity
* Department of Medical Pharmacology and Toxicology, College of Medicine, Texas A&M University System Health Science Center; and Department of Veterinary Anatomy and Public Health, College of Veterinary Medicine, Texas A&M University
Received March 2, 2004; accepted April 1, 2004
The cadherin/catenin complex is an essential regulator of intercellular adhesion and is critical for the establishment of epithelial cell polarity. The purpose of this study was to (1) determine the spatial pattern of cadherin and catenin expression, colocalization, and interaction along the mouse nephron, and (2) investigate the expression, localization, and interaction of proximal tubular cadherins and catenins during mercuric chloride-induced nephrotoxicity. Using a combination of Western blot analysis, colocalization studies, and coimmunoprecipitation, we conclude that two distinct cadherin/catenin complexes exist in adult mouse kidney proximal tubules: N-cadherin/ß-catenin/
-catenin and E-cadherin/ß-catenin/-catenin/p120-catenin. In the distal tubule, E-cadherin/ß-catenin/-catenin and E-cadherin/
-catenin/-catenin complexes are present. Male C3H mice were challenged with 0–25 µmol/kg mercuric chloride ip (6–48 h) to assess the impact of nephrotoxicity on cadherin/catenin complexes. Plasma creatinine and blood urea nitrogen were increased between 6 and 48 h, indicating the onset of renal failure. In addition, histological evaluation demonstrated alterations in the proximal tubules. At 24 h, we observed decreases in Ksp- and N-cadherin, but not in E-cadherin. Additionally, -catenin expression was decreased, in the absence of changes in ß-, -, and p120-catenin. The early stages (6 h) of mercuric chloride-induced nephrotoxicity were associated with disruption of complex integrity. N-cadherin and -catenin localizations were disrupted at 6 h. These changes in cadherin and catenin localization corresponded with a decrease in the coimmunoprecipitation of -catenin with both ß-catenin and N-cadherin. Interestingly, these changes occurred at the same time that aberrant staining of Na+/K+-ATPase staining was seen. Taken together, these data suggest that alterations in cadherin and catenin expression, localization, and interaction are associated with nephrotoxicity.
Key Words: cadherin; catenin; mercury; nephrotoxicity.
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