Variant (MDCK) kidney epithelial cells altered in response to inducers of dome formation and differentiation

Confluent cultures of the MDCK kidney epithelial cell line exhibit dome formation, a result of transepithelial fluid transport influenced by cell-cell and cell-substratum interaction. Dome formation was inducible by hexamethylene bisacetamide (HMBA) or dimethylformamide (DMF), compounds known as inducers of cell differentiation (Lever, 1979b). Analysis of the incidence of the dome-forming phenotype in colonies derived nonselectively from the MDCK cell line suggested that inducers recruit an increased fraction of the cell population to express dome formation. Variant MDCK cell lines were isolated which differed from the parental line in response to inducers while retaining cuboidal epithelial morphology. In five independently isolated and cloned MDCK variants, dome formation was not inducible by DMF and only marginally increased by HMBA. This phenotype was also associated with increased cell adhesiveness to a plastic substratum. Results from cocultivation experiments suggested that the DMF-unresponsive phenotype of variant cells may be partially overcome by cell-cell contact with wild-type cells. Sodium pump transport activity assessed by ouabain-sensitive Rb+ uptake was partially inhibited by HMBA and by DMF in a "wild-type" inducer-responsive clone. By contrast, DMF did not inhibit ouabain-sensitive Rb+ uptake in DMF-unresponsive variant clones, and sodium pump inhibition by HMBA was greatly diminished. This close correspondence between altered sodium pump modulation by inducers in variant clones and their altered dome-forming response reinforces our previous conclusions (Kennedy and Lever, 1984) that sodium pump modulation is closely associated with mechanisms of inducer action. Taken together, these findings implicate cell-cell interaction, cell-substratum interaction and sodium pump modulation in regulation of the differentiated phenotype of this cell line.