Role of insulin-like growth factor binding proteins in human post-nephrectomy proximal tubule cells

Unilateral nephrectomy results in a rapid and specific stimulation of growth and function of the remaining kidney (Ogden, 1967; Fine, 1986). In experimental animals, the bulk of such renal growth is accounted for by hypertrophy of the proximal tubule, which is detectable within 24-48 h and is preceded by an increase in proximal tubule sodium reabsorption via activated apical sodium-hydrogen exchange (NHE) (Fine, 1986; Pollock & Field, 1993). Although the existence of a kidney-specific humoral growth factor, which incites and/or regulates compensatory renal growth, has been long established by parabiotic experiments (Van Vroonhoven, Soler-Montesinos & Malt, 1972; Austin, Goldin & Preuss, 1981; Malt, 1983), serum injections in live animals (Lowenstein & Stern, 1963; Austin et al. 1981; Malt, 1983; Pollock, Nobes, Gyory, Heng & Field, 1996) and in vitro assays (Austin et al. 1981; Malt, 1983; Yamada, Kanetake, Saito, Kondo & Yamamoto, 1983; Yamamoto, Kanetake & Yamada, 1983; Yun, Areas, Yamamoto & Preuss, 1988; Esbrit, Garcia Ocana, Garcia Canero, Manzano & Jiminez Clavero, 1991; Garcia Ocana & Esbrit, 1994; Nobe, Pollock, Heng & Field, 1995), its precise identity remains elusive. Attempts at characterization have so far suggested that this factor is species specific (Yamamoto et al. 1983; Fine, 1986; Yun et al. 1988), unaffected by dialysis or heating (Fine, 1986), and possibly synthesized by the liver and activated by the remnant kidney in a time-dependent fashion following nephrectomy (Dicker, Morris & Shipolini, 1977; Fine, 1986; Garcia Ocana & Esbrit, 1992). Insulin-like growth factor-I (IGF-I), a 7.5 kDa peptide produced in the liver and kidney, exerts renotropic effects in proximal tubule cells (PTCs) and enhances Na+ reabsorption in in vitro and in vivo studies (Zumkeller & Schofield, 1992; Hammerman & Miller, 1993; Nobes et al. 1995; Feld & Hirschberg, 1996; Johnson et al. 1997b). A humoral role in the development of renal hypertrophy has been postulated since binding of IGF-I to PTCs is enhanced following reductions in renal mass (Polychronakos, Guyda & Posner, 1985; Hise, Lahn, Shao, Mantzouris & Fontana, 1993), endogenous renal cortical IGF-I accumulation precedes compensatory renal growth (Stiles, Sosenko, D'Ercole & Smith, 1985; Fagin & Melmed, 1987; Flyvbjerg, Thorlacius Ussing, Naeraa, Ingerslev & Orskov, 1988; Lajara et al. 1989; Zumkeller & Schofield, 1992; Feld & Hirschberg, 1996; Gronboek, Nielsen, Flyvbjerg & Orskov, 1997) and administration of a somatostatin analogue prevents compensatory renal growth and increased renal IGF-I content (Flyvbjerg, Frystyk, Thoracius Ussing & Orskov, 1989; Hammerman & Miller, 1993). Although serum IGF-I levels are reported to be either unchanged (Stiles et al. 1985; Fagin & Melmed, 1987; Lajara et al. 1989; Hammerman & Miller, 1993; Gronboek et al. 1997) or decreased (Flyvbjerg et al. 1988) and renal IGF-I mRNA levels are either unchanged (Lajara et al. 1989) or increased (Fagin & Melmed, 1987) following reductions in renal mass, the accumulation and enhanced action of IGF-I at the proximal tubule following uninephrectomy might be explained by alterations in circulating levels of IGF binding proteins (IGFBPs), which tightly regulate the delivery of serum IGF-I to tissues (Jones & Clemmons, 1995; Feld & Hirschberg, 1996). Circulating IGF-I may then be trapped in the proximal tubule by post-nephrectomy increases in IGF receptor number/affinity or in cell-associated IGFBPs, which potentiate IGF-I action on PTCs (Johnson et al. 1997c). However, the circulating levels of IGFBPs following unilateral nephrectomy and their effects on IGF-I binding to PTCs have not been studied to date. Therefore, the aim of the present study was to determine whether alterations in the IGF-I/IGFBP axis and its direct interaction with human PTCs account for the renotropic effect of serum following a reduction of renal mass.