The noble gas xenon has been shown to be protective in preconditioning settings against renal ischemic injury. The aims of this study were to determine the protective effects of the other noble gases, helium, neon, argon, krypton and xenon, on human tubular kidney HK2 cells in vitro. Cultured human renal tubular cells (HK2) were exposed to noble gas preconditioning (75% noble gas; 20% O(2); 5% CO(2)) for three hours or mock preconditioning. Twenty-four hours after gas exposure, cell injury was provoked with oxygen-glucose deprived (OGD) culture medium for three hours. Cell viability was assessed 24 h post-OGD by a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Other cohorts of cultured cells were incubated in the absence of OGD in 75% noble gas, 20% O(2) and 5% CO(2) and cellular signals phospho-Akt (p-Akt), hypoxia-inducible factor-1alpha (HIF-1alpha) and Bcl-2 were assessed by Western blotting. OGD caused a reduction in cell viability to 0.382 +/- 0.1 from 1.0 +/- 0.15 at control (P < 0.01). Neon, argon and krypton showed no protection from injury (0.404 +/- 0.03; 0.428 +/- 0.02; 0.452 +/- 0.02; P > 0.05). Helium by comparison significantly enhanced cell injury (0.191 +/- 0.05; P < 0.01). Xenon alone exerted a protective effect (0.678 +/- 0.07; P < 0.001). In the absence of OGD, helium was also detrimental (0.909 +/- 0.07; P < 0.01). Xenon caused an increased expression of p-Akt, HIF-1alpha and Bcl-2, while the other noble gases did not modify protein expression. These results suggest that unlike other noble gases, preconditioning with the anesthetic noble gas xenon may have a role in protection against renal ischemic injury.