Objectives: Oxidative stress in renal tubular cells is known to be one of the etiologies of diabetic nephropathy and acute kidney injury. 2-Deoxy-D-ribose (dRib) causes oxidative damage by depleting GSH in cells, including beta cells. System χc- is a membrane transporter that moves extracellular cystine into cells independent of sodium, and cystine uptake through system χc- is a rate-limiting step for intracellular GSH synthesis, which is important for protecting cells from oxidative stress. We conducted this study to determine whether dRib causes oxidative damage in renal tubular cells and, specifically, to investigate the mechanism through which dRib increases oxidative stress.  Methods: L-[14C]cystine uptake, GSH content, reactive oxygen species (ROS) levels, and cell viability were measured in NRK-52E cells, a renal tubular cell line, and the mRNA and protein expression of xCT, the functional unit of system χc-, were investigated. The xCT gene was then overexpressed in NRK-52E cells using lentivirus. L-[14C]cystine uptake, GSH, and cell viability were also measured in primary renal tubular epithelial cells isolated from rats. Results: When NRK-52E cells were stimulated with various concentrations of dRiB, L-[14C]cystine uptake  decreased, mRNA and protein expression of xCT increased, and intracellular GSH and ROS levels and cell viability were significantly decreased in a dose-dependent manner. L-[14C]cystine uptake, intracellular GSH and ROS levels, and cell viability reduced by dRib were all significantly recovered by xCT overexpression. In primary renal tubular epithelial cells, dRiB also significantly reduced L-[14C]cystine uptake, GSH content, and cell viability, and these were almost completely recovered by pretreatment with 2-mercaptoethanol. Conclusions: In renal tubular epithelial cells, dRib depletes GSH by reducing cystine uptake through inhibition of xCT. The resulting oxidative damage can be prevented by overexpressing xCT. Therefore, it is thought that the oxidative damage in renal tubular cells can be prevented through system x(c)- regulation.