title: An IGF-I antagonist does not inhibit renal fibrosis in the rat following subtotal nephrectomy.
abstract: Insulin-like growth factor I (IGF-I) has been proposed as a mediator of kidney scarring, although no interventional studies on the role of IGF-I in models of chronic kidney disease have been reported. The effect of a peptide IGF-I receptor antagonist (JB3) has been examined on kidney fibrosis and function in the rat following 5/6 subtotal nephrectomy (SNx). Male Wistar rats were anesthetized with halothane and subjected to SNx. JB3 was delivered by subcutaneous infusion using Alzet osmotic minipumps. In vitro studies showed JB3 to displace (125)I-IGF-I binding to isolated rat glomeruli and to inhibit IGF-I-induced receptor phosphorylation in renal tubular cells in culture. In the 7-day SNx rats, IGF-I immunostain was present in collecting tubules and JB3 inhibited compensatory renal growth, the maximum effect occurring at 10 microg. kg(-1).day(-1). After 90 days, the SNx rats developed proteinuria, hypertension, and a fall in glomerular filtration rate. IGF-I immunostain was present in the tubulointerstitial space of the remnant kidney together with marked tubulointerstitial fibrosis. Treatment with JB3 at a dose of 10 microg. kg(-1).day(-1) had no effect on the renal fibrosis measured by Masson's trichrome staining or immunostain for collagen III and collagen IV. The proteinuria, hypertension, and lower creatinine clearance all remained unchanged. The remnant kidney was associated with a 50% decrease in renal IGF-I mRNA, which was partially restored by treatment with JB3. Thus an interventional study with an IGF-I receptor antagonist does not support a role for IGF-I in the development of renal fibrosis in the SNx rat, although IGF-I does make an important contribution to compensatory kidney growth.
authors.affiliation: School of Allied Health Sciences, De Montfort University, Leicester, UK.
authors.forename: Simon D
authors.initials: SD
authors.lastname: Oldroyd
authors.forename: Yohie
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Arthur
authors.initials: A
authors.lastname: Moir
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Johnson
authors.forename: A Meguid
authors.initials: AM
authors.lastname: El Nahas
authors.forename: John L
authors.initials: JL
authors.lastname: Haylor
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005355:Fibrosis / Q000517:prevention & control; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000502:physiology*; D007668:Kidney / Q000473:pathology*; D008297:Male; D009392:Nephrectomy; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D009842:Oligopeptides; D007334:Insulin-Like Growth Factor I