Animal living in desert environments are forced to survive despite severe heat, intense solar radiation, and both acute and chronic dehydration. Indeed, 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 by which we subjected reproductively mature adults to profound acute dehydration, during which they lost on average 23% of their body weight. Animals react via a series of changes in the kidney, which include modulating expression of genes responsible for reducing the rate of transcription, and maintaining water and salt balance. Extracellular matrix turnover appears to be decreased, and apoptosis is limited. Serum Creatinine and other biomarkers of kidney injury are not elevated, which is different than the canonical human response, suggesting that transcriptional changes caused by acute dehydration effectively prohibit widespread kidney damage in the cactus mouse.