Glomerular ultrafiltration of IGF-I may contribute to increased renal sodium retention in diabetic nephropathy

Insulin-like growth factor-1 (IGF-1) is found in plasma at relatively high levels (similar to 40 nmol/L) but <1% is present in the free form and >99% is bound to specific binding proteins to form high-molecular-weight complexes of similar to 50 and similar to 150 kd. We hypothesized that in rats with diabetic nephropathy but not in normal animals, IGF-1-containing binding protein complexes undergo glomerular ultrafiltration, allowing the peptide to interact with IGF-1 receptors in apical tubular membranes. By this route, ultrafiltered IGF-1 may increase tubular epithelial cell sodium absorption in overt diabetic nephropathy. In serum samples from diabetic rats, IGF-1 levels (227 +/- 34 ng/ml) were reduced as compared with control levels (319 +/- 33 ng/mL, P = .05), and IGF-binding protein-2 (IGFBP-2) is increased about 2-fold. In diabetic rats, IGF-I undergoes glomerular ultrafiltration and is present in proximal tubular fluid that was collected by nephron micropuncture at 2.54 +/- 0.54 nmol/L but is below the detection limit in tubular fluid from normal rats. IGFBP-1, IGFBP-2, IGFBP-3, and IGFBP-4 are all present in diabetic rat glomerular ultrafiltrate, but IGFBP-2 levels are greater than those of each of the other three IGFBPs. Neither recombinant human IGF-l (1 nmol/L) nor diabetic rat glomerular ultrafiltrate affect sodium transport in cultured mouse proximal tubular cells. In contrast, rhIGF-1 and diabetic rat glomerular ultrafiltrate increase the apical-to-basolateral transport of Na-22(+) in distal tubule-like Ag cells through mechanisms involving apical IGF-1 receptors. In normal rats, luminal infusion with rhIGF-1 or with diabetic rat glomerular ultrafiltrate into late proximal tubules increases distal tubular Na+ absorption. These findings indicate that diabetic glomerular sclerosis causes glomerular ultrafiltration of IGF-1, and they suggest that tubular fluid IGF-1 may contribute to sodium (and fluid) retention that is commonly observed in patients with severe diabetic nephropathy.