Insulin-like growth factor-1 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) with a concomitant increase in DNA synthesis. Interactions between growth 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 minutes 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 micrograms/kg) or normal saline solution (NS, 0.2 ml) was given by intravenous bolus, followed by twice daily subcutaneous injections of IGF-1 (50 micrograms/kg) or 0.2 ml NS for 4 days, respectively, in IGF-1-Tx) and NS treated (NS-Tx) groups (n = 8 each). On the day after the completion of treatment, inulin clearance (ml/kg/min) of the postischemic 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 enhanced 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 after the injury. EGF-R tyrosine phosphorylation (which reflects receptor activation) increased in postischemic kidneys in both NS-Tx (n = 5) and IGF-1-Tx (n = 3) groups 1 day after the injury as compared with nonischemic contralateral kidneys. In the IGF-1-Tx group there was also increased iodine 125-labeled EGF binding and EGF-R protein. Our results demonstrate a beneficial effect of IGF-1 on postischemic ARF. Furthermore, they suggest that EGF-R activation is involved in tubular regeneration and that IGF-1 may enhance EGF-R activation by increasing EGF-R expression.
Lin
J J
JJ
Department of Pediatrics, State University of New York at Stony Brook 11794, USA.
Cybulsky
A V
AV
Goodyer
P R
PR
Fine
R N
RN
Kaskel
F J
FJ
D058186:Acute Kidney Injury / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007457:Iodine Radioisotopes; D007511:Ischemia / Q000503:physiopathology*; D007679:Kidney Medulla / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D019000:Phosphotyrosine; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration / Q000187:drug effects*; D012079:Renal Circulation; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
D007457:Iodine Radioisotopes; D019000:Phosphotyrosine; D014443:Tyrosine; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D004247:DNA; D066246:ErbB Receptors