EFFECT OF INSULIN-LIKE-GROWTH-FACTOR BINDING-PROTEINS ON THE RESPONSEOF PROXIMAL TUBULAR CELLS TO INSULIN-LIKE GROWTH-FACTOR-I

The insulin-like growth factor binding proteins (IGFBP) are major modu lators of insulinlike growth factor-I (IGF-I) action, but relatively l ittle is known about their production by kidney tubular cells or about their modulating effects on the action of IGF-I on these cells. In th is study we demonstrated that rabbit proximal tubular cells express th e genes for IGFBP-2 -4 and -5 and secrete 24 and 32 kDa size binding p roteins. The rate of IGFBP production by these cells was regulated by several growth factors including hydrocortisone, which was potently st imulatory, and EGF, which was inhibitory. The overall effect of these kidney cell-secreted IGFBPs was to inhibit the mitogenic activity of I GF-I. Similarly, recombinant IGFBP-3, the major circulating IGFBP that in kidney is produced close to the proximal tubules, also inhibited I GF-I stimulated DNA synthesis in cultured rabbit proximal tubular cell s and in cultured opossum kidney (OK) cells. IGFBP-3 also inhibited ba sal DNA synthesis in OK cells in the absence of added IGF-I, suggestin g that this IGFBP may have an IGF-I independent action. These findings highlight the important effect that IGFBPs have on the action of IGF- I on kidney cells and support the notion that the changes in IGFBPs ob served in various renal diseases may contribute to the pathophysiology of these diseases.