Glomerular ultrafiltration of IGF-I may contribute to increased renal sodium retention in diabetic nephropathy.
Insulin-like growth factor-I (IGF-I) is found in plasma at relatively high levels (approximately 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 approximately 50 and approximately 150 kd. We hypothesized that in rats with diabetic nephropathy but not in normal animals, IGF-I-containing binding protein complexes undergo glomerular ultrafiltration, allowing the peptide to interact with IGF-I receptors in apical tubular membranes. By this route, ultrafiltered IGF-I may increase tubular epithelial cell sodium absorption in overt diabetic nephropathy. In serum samples from diabetic rats, IGF-I 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-I (1 nmol/L) nor diabetic rat glomerular ultrafiltrate affect sodium transport in cultured mouse proximal tubular cells. In contrast, rhIGF-I and diabetic rat glomerular ultrafiltrate increase the apical-to-basolateral transport of 22Na+ in distal tubule-like A6 cells through mechanisms involving apical IGF-I receptors. In normal rats, luminal infusion with rhIGF-I 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-I, and they suggest that tubular fluid IGF-I may contribute to sodium (and fluid) retention that is commonly observed in patients with severe diabetic nephropathy.
Wang
S N
SN
Division of Nephrology and Hypertension, Harbor-UCLA Medical Center, Torrance 90509, USA.
Lapage
J
J
Hirschberg
R
R
D000818:Animals; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000032:analysis / Q000378:metabolism; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000032:analysis / Q000378:metabolism; D018969:Insulin-Like Growth Factor Binding Proteins / Q000032:analysis / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism*; D007686:Kidney Tubules, Distal / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008297:Male; D009399:Nephrons / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism*; D014462:Ultrafiltration
D018970:Insulin-Like Growth Factor Binding Protein 1; D018971:Insulin-Like Growth Factor Binding Protein 2; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I; D012964:Sodium