Loss of homotypic epithelial cell adhesion by selective N-cadherin displacement in bismuth nephrotoxicity

The nephrotoxicity of single high doses of bismuth (Bi)-containing therapeu tic drugs is characterized morphologically by detachment of proximal tubula r epithelial cells (PTECs) from each other, followed by cell death. We inve stigated whether Bi nephrotoxicity is mediated by changes in the distributi on of proteins involved in intercellular adhesion. A nephrotoxic dose of co lloidal bismuth subcitrate (CBS; 3.0 mmol Bi/kg) was orally administrated t o 10 female Wistar rats. After 1 h, N-cadherin had disappeared from the adh erence junctions of vital PTECs, whereas ZO-1, a tight junction marker, rem ained present at the cell-cell border until cell death occurred after 3 h. E-Cadherin, absent in PTECs, remained absent. Exposure of the renal epithel ial cell lines NRK-52E and LLC-PK1 to 400 muM Bi3+ also resulted in the dis appearance of N-cadherin expression after I h, whereas ZO-1, E-cadherin, an d Desmoplakin expression did not resolve before cell death at 24 h, thus co nfirming in vivo results. Our results are the first to indicate that Bi-ind uced death of PTECs is preceded by redistribution of N-cadherin and the dis ruption of homotypic cell adhesion. (C) 2001 Academic Press.