Effects of tumor promoters on LLC-PK1 renal epithelial tight junctions and transepithelial fluxes.

The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) irreversibly dissipates the electrical potential difference (PD) across LLC-PK1 renal epithelial cell sheets in a dose-dependent manner. The promoter is equally effective when presented to either cell surface. TPA is also equally effective at dissipating the apical-negative PD or the heretofore undescribed apical-positive PD, both of which can exist spontaneously across this monolayer. Diffusion potentials arising from imposed NaCl gradients across LLC-PK1 cell sheets are likewise reduced by TPA. The non-tumor-promoting parent compound, phorbol, is ineffective, but the more hydrophilic TPA analogue, phorbol 12,13-dibutyrate (PDBU) is as effective as TPA. Unlike TPA, the effects of PDBU are reversible. By observing the (paracellular) fluxes of D-mannitol and polyethylene glycol, these effects on PD are shown to be due to increased permeability of the tight junctions. This effect is immediately reversible once PDBU is removed. These findings are discussed in light of the ramifications of the breakdown of epithelial compartments in vivo and the role this could play in the regulation of epithelial cell growth.