Influence of hypophysectomy on renal proteoglycans and their modulation by insulin-like growth factor-I and its receptor.

Abstract

Hypophysectomy leads to growth retardation of the animals, which is believed to be related to the deficiency of certain growth factors influencing the metabolism and synthesis of glycoproteins. Conceivably, the extracellular matrix proteins (ECM) are also affected, in particular the sulfated proteoglycans (PGs). In this study, we investigated the status of the ECM proteins and sulfated PGs, and the expression and de novo synthesis of insulin-like growth factor-I (IGF-I) receptor (IGF-IR) in hypophysectomized (Hx) rats. The studies were extended to ascertain the effect of IGF-I on the de novo synthesis of glomerular ECM glycoproteins in Hx rats. An organ perfusion system was used in which isolated rat kidneys were radiolabeled with either [35S]sulfate or [35S]methionine, after which IGF-IR and ECM macromolecules were isolated and characterized by biochemical and tissue autoradiographic procedures. Hypophysectomy resulted in a fall in IGF-I levels in serum and isolated renal glomeruli. Reduced synthesis of ECM proteins, i.e. type IV collagen, laminin, and sulfated PGs, and reduced synthesis and mRNA expression of IGF-IR were observed in the glomeruli of the Hx rats. Tissue autoradiographic studies revealed a reduced grain density (concentration of radiation) over various cell types of the glomerulus. After inclusion of IGF-I in the perfusion medium not only was synthesis restored to normal in Hx rats, but it far exceeded the control basal values in the intact animals. Under the influence of IGF-I, the magnitude of increased synthesis of the ECM proteins, in particular the sulfated PGs, was highly accentuated in the kidneys of the Hx group compared to the controls. Also, a remarkably increased [35S]sulfate incorporation was observed in the glomerular mesangial cells. The analysis of IGF-IR by specific binding studies revealed a decreased concentration of the receptors, but an increased IGF-I-binding affinity, the latter of which probably contributed to the IGF-I-induced accentuated synthesis of renal glomerular PGs in the Hx group.