Animals living in desert environments are forced to survive despite severe heat, intense solar radiation, and both acute and chronic dehydration. These animals have evolved phenotypes that effectively address these environmental stressors. To begin to understand the ways in which the desert-adapted rodent P. eremicus survives, we performed an experiment where we subjected reproductively mature adults to 72 hours of water deprivation, during which they lost on average 23% of their body weight. The animals reacted via a series of changes in the kidney, which included modulating expression of genes responsible for reducing the rate of transcription and maintaining water and salt balance. Extracellular matrix turnover appeared to be decreased, and apoptosis was limited. Serum creatinine and other biomarkers of kidney injury were not elevated, which is different than the canonical human response, suggesting that changes in gene expression related to acute dehydration may effectively prohibit widespread kidney damage in the cactus mouse.