Cadmium alters the localization of N-cadherin, E-cadherin, and beta-catenin in the proximal tubule epithelium.
Recent studies on proximal tubule-derived cells in culture have shown that Cd has relatively specific damaging effects on the cadherin-dependent junctions between the cells. The objective of the present study was to determine whether Cd can affect cadherin-dependent junctions in the proximal tubule epithelium in vivo. Male Sprague-Dawley rats received subcutaneous injections of Cd (0.6 mg/kg in isotonic saline, 5 days per week for up to 6 weeks). One day each week, 24-h urine samples were collected and analyzed for protein and creatinine. After 5-6 weeks, the Cd-treated animals developed significant proteinuria, with no change in creatinine excretion. Visualization of pan-cadherin immunoreactive materials by immunoperoxidase labeling showed that Cd caused a marked reduction in the intensity of cadherin labeling associated with the apical and the basolateral surfaces of the epithelial cells of the proximal tubule, but no change in the pattern of cadherin labeling in other segments of the nephron. Results of studies utilizing specific antibodies against N-cadherin, E-cadherin, and beta-catenin showed changes in the localization of all three molecules in the proximal tubule. Assessment of cell membrane integrity with trypan blue and ethidium homodimer showed no overt evidence of death in the proximal tubule epithelial cells. Additional results showed that Cd caused only a slight increase in the total levels of glutathione and no significant peroxidation of membrane lipids, indicating only a modest level of oxidative stress. These results indicate that Cd can disrupt cadherin-dependent cell-cell junctions in the proximal tubule, and they raise the possibility that a loss of cadherin-mediated adhesion may contribute to the nephrotoxic effects of Cd.
Prozialeck
Walter C
WC
Department of Pharmacology, Midwestern University, 555 31st Street, Downers Grove, IL 60515, USA. wprozi@midwestern.edu
Lamar
Peter C
PC
Lynch
Sean M
SM
D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002104:Cadmium / Q000633:toxicity*; D002463:Cell Membrane Permeability / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D051176:beta Catenin
D015820:Cadherins; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D017392:Thiobarbituric Acid Reactive Substances; D015534:Trans-Activators; D051176:beta Catenin; D002104:Cadmium; D005978:Glutathione