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

Abstract

In order to determine the role of the insulin‐like growth factor‐I (IGF‐I)/IGF binding protein (IGFBP) axis in the augmentation of tubule growth and function following reductions in nephron mass, primary cultures of human proximal tubule cells (PTCs) were generated from the histologically normal sections of ten surgically removed kidneys. PTC hypertrophy (cellular protein content), DNA synthesis (thymidine incorporation) and apical sodium‐hydrogen exchange (NHE) activity (ethylisopropylamiloride‐sensitive apical 22Na+ uptake) were measured following 24 h incubation in media supplemented with 10 % pre‐ or post‐nephrectomy sera obtained from these patients. The results were compared with the effects of pre‐ and post‐operative control sera collected from seven patients undergoing retroperitoneal operations not involving removal of renal tissue. Day 1 post‐nephrectomy sera promoted a significant 73 % increase in apical NHE activity, which was accompanied by a significant increase in PTC binding of 125I‐IGF‐I (post‐ vs. pre‐nephrectomy, 163 ± 6 vs. 142 ± 4 fmol (mg protein)−1; P < 0.05). Subsequent post‐nephrectomy sera significantly stimulated PTC protein content and thymidine incorporation, peaking at day 7 (127.7 ± 14.0 and 118.4 ± 9.0 % of pre‐nephrectomy values, respectively; P < 0.05). The growth effects were cell specific, as they were not observed with renal cortical fibroblasts. No change was detected in any of these measured variables following exposure to control sera. Serum IGF‐I and IGFBP‐1 levels did not significantly change over time or between groups. IGFBP‐3 levels progressively decreased in both control and nephrectomized sera from pre‐operative values of 3580 ± 305 and 3360 ± 217 ng ml−1, respectively, to 2670 ± 341 and 2600 ± 347 ng ml−1 at 1 week post‐operation. Serum IGFBP‐2 levels increased to a comparable extent in both controls (day 0 vs. day 7, 2940 ± 1024 vs. 7010 ± 2520 ng ml−1; P < 0.01) and nephrectomized patients (day 0 vs. day 7, 3070 ± 656 vs. 9130 ± 2010 ng ml−1; P < 0.01). The results indicate that nephrectomy engenders the elaboration of one or more humoral factor(s), which promotes increased binding of IGF‐I to PTCs and which may in turn specifically stimulate PTC Na+ transport and growth.

Growth factors in progressive renal disease

“…Insulin‐like growth factor‐I (IGF‐I) production in the kidney has been localized to the medullary and cortical collecting ducts, thick ascending limb of Henle's loop, glomerular mesangium and renal cortical fibroblasts 12 . Its actions are potentiated or inhibited by a family of six distinct IGF binding proteins (IGFBPs) and three IGFBP‐related proteins (all produced in the kidney) and include stimulation of tubulointerstitial growth and extracellular matrix production, inhibition of matrix degradation, augmentation of glomerular filtration rate (GFR) and renal plasma flow, and stimulation of proximal tubule sodium reabsorption and energy consumption 12–14 . Extractable renal IGF‐I is increased in a number of models of renal disease, including subtotal nephrectomy, diabetic nephropathy and cyclosporine nephropathy 5,12 .…”

“…12 Its actions are potentiated or inhibited by a family of six distinct IGF binding proteins (IGFBPs) and three IGFBPrelated proteins (all produced in the kidney) and include stimulation of tubulointerstitial growth and extracellular matrix production, inhibition of matrix degradation, augmentation of glomerular filtration rate (GFR) and renal plasma flow, and stimulation of proximal tubule sodium reabsorption and energy consumption. [12][13][14] Extractable renal IGF-I is increased in a number of models of renal disease, including subtotal nephrectomy, diabetic nephropathy and cyclosporine nephropathy. 5,12 The combination of diabetes and unilateral nephrectomy induces an additive stimulation of renal IGF-I content, hypertrophy and scarring 15 and correlations have been observed between the degree of renal IGF-I accretion and the severity of diabetes or renal ablation.…”