JB3, an IGF-I receptor antagonist, inhibits early renal growth in diabetic and uninephrectomized rats

Abstract

Biochemical evidence suggests that insulin-like growth factor I (IGF-I) may play an important role as a mediator of kidney growth. In the present study, an IGF-I receptor antagonist (JB3) was synthesized, and its effect on the renal growth that follows the induction of diabetes or unilateral nephrectomy (UNx) was examined. JB3 was generated by solid phase peptide synthesis. Its activity as an IGF-I antagonist was confirmed in an opossum kidney cell line from its inhibitory effect on the increase in thymidine incorporation into DNA induced by recombinant human IGF-I. Male Wistar rats were anesthetized with halothane and subjected to either the induction of diabetes by streptozotocin (intravenous 60 mg/kg) for 4 d (control animals received citrate buffer) or UNx for 11 d (control animals were sham operated). JB3 was delivered by subcutaneous infusion using an osmotic minipump implanted 3 d before the induction of diabetes or UNx. Kidney wet weight, DNA, and protein all were significantly higher 4 d after the induction of diabetes (24%) or 11 d after UNx (55%). Dose-response studies (1 to 30 μg/kg per day) showed JB3 administration to inhibit the increase in kidney growth in both diabetic and UNx rats. The increase in kidney wet weight, DNA, and protein was significantly lower in UNx rats that were treated with JB3 10 μg/kg per day (P <0.05) than in saline vehicle controls but was abolished in diabetic rats that were treated with JB3 3 μg/kg per day (P <0.01). Increasing the dose of JB3 to 30 μg/kg per day was associated with a decrease in its inhibitory effect, resulting in bell-shaped dose-response curves. JB3 administration had no effect on the blood glucose concentration or food consumption by either diabetic or nondiabetic animals. The results support the concept of IGF-I as an important mediator of the early renal growth that follows the induction of diabetes or UNx in the rat.