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Treatment with ouabain led to massive death of principal cells from collecting ducts (C7-MDCK), indicated by cell swelling, loss of mitochondrial function, an irregular pattern of DNA degradation, and insensitivity to pan-caspase inhibitor. Equimolar substitution of extracellular Na⁺ by K⁺ or choline⁺ sharply attenuated the effect of ouabain on intracellular Na⁺ and K⁺ content but did not protect the cells from death in the presence of ouabain. In contrast to ouabain, inhibition of the Na⁺/K⁺ pump in K⁺-free medium increased Na⁺_i content but did not affect cell survival. In control and K⁺-free medium, ouabain triggered half-maximal cell death at concentrations of ∼0.5 and 0.05μM, respectively, which was consistent with elevation of Na⁺/K⁺ pump sensitivity to ouabain in K⁺-depleted medium. Our results show for the first time that the death of ouabain-treated renal epithelial cells is independent of the inhibition of Na⁺/K …