We previously reported that following bilateral acute tubular necrosis (ATN) profound changes in the intrarenal insulin-like growth factor-I axis occurs which are unrelated to altered nutritional intake. In this current report we studied rats with unilateral ATN to assess whether these changes reflect a response to acute injury or the accompanying uremia. Compared to the contralateral kidney, the injured kidney showed an increase in IGF-I receptor number without a change in IGF-I receptor mRNA levels, a decrease in IGF-I mRNA and IGF-I protein levels, a decrease in growth hormone (GH) receptor mRNA abundance and receptor binding. There was also a decrease in IGF binding protein-2, -3 and -5 mRNA levels together with a fall in protein products. Since this unilateral ATN model excludes the influence of uremia and reduced nutritional intake, we surmised that these changes reflect a direct response to injury. Next, because of the reduced GH receptor binding noted above and the reported decrease in epidermal growth factor (EGF) expression in ATN, we tested the thesis that the low kidney IGF-I mRNA levels in ATN are partly due to a relative or absolute deficiency of these hormones. Administration of EGF or GH promptly increased ATN kidney IGF-I mRNA levels to control kidney values, lending support to the thesis. The response to EGF also suggests that the salutary effect of EGF treatment in ATN may partly be mediated by stimulating IGF-I production.