TROPHIC EFFECT OF INSULIN-LIKE GROWTH-FACTOR-I ON METANEPHRIC DEVELOPMENT - RELATIONSHIP TO PROTEOGLYCANS

Many hormones/factors influence the total body growth and development during embryonic life, and very few studies have been carried out to a scertain their effects on the individual organ system. In this study, the effect of exogenous insulin-like growth factor-I (IGF-I) on embryo nic kidneys was investigated, and correlated with phenotypic and gene expression and synthesis of extracellular matrix (ECM) proteoglycans ( PGs). Antisense experiments were carried out to elucidate the role of endogenous (IGF-I in metanephric development. Mouse metanephroi, harve sted at 13th day of gestation, were exposed to IGF-I (100 ng/ml) in an organ culture for 7 days. An enlargement of the metanephroi with acce ntuation of its lobules, and increase in the nephron population and [H -3]thymidine incorporation was observed. Immunofluorescence studies an d Southern blot analysis of polymerase chain reaction products indicat ed augmented expression of the ECM PGs. A heavy concentration of [S-35 ]sulfate-associated radioactivity over the tips of ureteric bud branch es and ECM components of maturing glomeruli was seen. Maximal effect o f radioincorporation was observed on day-4 of the culture, the period when the concentration of endogenous IGF-I is the highest. PGs synthes ized had elevated proportions of chondroitin sulfate vs heparan sulfat e and of free chains, and reduced charge-density characteristics. Immu noprecipitation studies of [S-35]methionine-labeled glycoproteins reve aled an increased synthesis of core-peptide of the PGs. IGF-I antisens e oligonucleotide caused retardation in the growth of the kidneys alon g with the decrease in de novo synthesis of PGs. These findings indica te that IGF-I, a polypeptide essential to the renal growth and develop ment, has a trophic effect on the embryonic kidney during the postindu ctive period of metanephric development, and the observed response has a temporal relationship with the increased synthesis of the PGs,