INSULIN-LIKE GROWTH-FACTOR-I ENHANCES EPIDERMAL GROWTH-FACTOR RECEPTOR ACTIVATION AND RENAL TUBULAR CELL REGENERATION IN POSTISCHEMIC ACUTE-RENAL-FAILURE

Growth factors such as insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), and hepatocyte growth factor have been shown to accelerate the recovery from postischemic acute renal failure (ARF) wi th a concomitant increase in DNA synthesis. Interactions between growt h factors have been demonstrated in a number of in vitro studies. This study examined the effect of exogenous IGF-1 on the DNA synthesis and EGF receptor (EGF-R) activation in postischemic rat kidneys. Thirty m inutes after the relief of 30-minute total occlusion of the left renal artery in anesthetized 225 to 300 gm Sprague-Dawley rats, either IGF- 1 (75 mu g/kg) or normal saline solution (NS, 0.2 mi) was given by int ravenous bolus, followed by twice daily subcutaneous injections of IGF -1 (50 mu g/kg) or 0.2 ml NS for 4 days, respectively, in IGF-1 treate d (IGF-1-Tx) and NS treated (NS-Tx) groups (n = 8 each). On the day af ter the completion of treatment, inulin clearance (ml/kg/min) of the p ostischemic kidneys in the IGF-1-Tx group was significantly higher (p < 0.01) than inulin clearance of kidneys in the NS-Tx group. This was associated with improved kidney morphology. IGF-1 treatment also enhan ced the labeling index of 5-bromo-2'-deoxyuridine (percent of stained tubule cells), a marker for active DNA synthesis, in the outer medulla of postischemic kidneys at 1 day and 2 days offer the injury. EGF-R t yrosine phosphorylation (which reflects receptor activation) increased in postischemic kidneys in both NS-Tx (n = 5) and IGF-1-Tx (n = 3) gr oups 1 day after the injury as compared with nonischemic contralateral kidneys. In the IGF-1-Tx group there was also increased iodine 125-la beled EGF binding and EGF-R protein. Our results demonstrate a benefic ial effect of IGF-1 on postischemic ARF. Furthermore, they suggest tha t EGF-R activation is involved in tubular regeneration and that IGF-1 may enhance EGF-R activation by increasing EGF-R expression.