Following loss of functional renal mass due to acute injury, there is significantly increased proliferation of tubular epithelium to replace injured and necrotic cells. In contrast, following uninephrectomy, the contralateral kidney increases in size primarily by hypertrophy, with little cellular proliferation. We and others have demonstrated only modest increases in renal protooncogene expression following uninephrectomy. In this study, we demonstrate markedly elevated expression of the protooncogenes c-fos, c-myc, c-Ki-ras, and c-Ha-ras following acute renal injury induced by a single large parenteral dose of folic acid. The expression of these genes occurs in a sequential pattern similar to that seen in proliferating cells in culture and in regenerating liver. In addition, we demonstrate elevated levels of histone H4 and beta-actin mRNAs consistent with increased cell proliferation. These data suggest that the molecular mechanisms regulating cell proliferation in the kidney are similar to those in regenerating liver and in cultured cells. In addition, it appears that these events are regulated normally after acute renal injury and following uninephrectomy, since in both instances the levels of protooncogene expression correlate with the degree of cell proliferation. This is in direct contrast to a pathologic renal condition, polycystic kidney disease, in which the level of protooncogene expression is out of proportion to the degree of cell proliferation. Further studies of the molecular correlates of acute renal injury may yield insight into the pathogenesis of this and other clinically important renal disorders.