Acute tubular damage is a major cause of renal failure, especially at the early phase of kidney transplant when ischemia-reperfusion injury and cyclosporin A toxicity may coexist. The mechanisms of the latter are largely unknown. Using an mRNA microarray on microdissected tubules from a rat model of cyclosporin A toxicity to describe the related epithelial-specific transcriptional signature in vivo, we found that cyclosporin A induces pathways dependent on the transcription factor ATF4 and identified nuclear protein transcriptional regulator 1 (Nupr1), a stress response gene induced by ATF4, as the gene most strongly upregulated. Upon cyclosporin A treatment, Nupr1-deficient mice exhibited worse renal tubular lesions than wild-type mice. In primary cultures treated with cyclosporin A, renal tubular cells isolated from Nupr1-deficient mice exhibited more apoptosis and ATP depletion than cells from wild-type mice. Furthermore, cyclosporin A decreased protein synthesis and abolished proliferation in wild-type tubular cells, but only reduced proliferation in Nupr1-deficient cells. Compared with controls, mouse models of ischemia-reperfusion injury, urinary obstruction, and hypertension exhibited upregulated expression of renal NUPR1, and cyclosporin A induced Nupr1 expression in cultured human tubular epithelial cells. Finally, immunohistochemical analysis revealed strong expression of NUPR1 in the nuclei of renal proximal tubules of injured human kidney allografts, but not in those of stable allografts. Taken together, these results suggest that epithelial expression of NUPR1 has a protective role in response to injury after renal transplant and, presumably, in other forms of acute tubular damage.