HUMAN RENAL FIBROBLASTS MODULATE PROXIMAL TUBULE CELL-GROWTH AND TRANSPORT VIA THE TGF-I AXIS

To determine the paracrine interactions involved in the tubulointersti tial response to progressive renal disease, the role of insulin-like g rowth factor-I (IGF-I) and its binding proteins (IGFBPs) in in vitro i nteractions between human proximal tubule cells (PTC) and renal cortic al fibroblasts (CF) were studied in primary cell culture. PTC growth a nd transport were increased in the presence of CF-conditioned media (C F-CM), as shown by increased thymidine incorporation, cellular protein content and sodium-hydrogen exchange (NHE) activity, to 185 +/- 31% ( P < 0.01), 150 +/- 18% (P < 0.05) and 195 +/- 27% (P < 0.01) of the co ntrol values. respectively. IGF-I was produced by cultured CF at a rat e of 64.6 +/- 7.5 ng/mg protein/day. Exogenous IGF-I applied to PTC pr ovoked similar enhancement of growth and NHE activity as CF-CM and the stimulatory effect of CF-CM was blocked by specific immunoneutralizat ion of IGF-I receptors. These receptors were threefold more abundant o n PTC basolateral versus apical membranes. IGF binding proteins (IGFBP )-2 and IGFBP-3 were secreted by CF at rates of 694 +/- 88 and 1769 +/ - 45 ng/mg/day, with the release of IGFBP-3 being enhanced in the pres ence of PTC-CM (120.0 +/- 9.7% of control, P < 0.01). Moreover, the ad dition of CF-CM to PTC increased cell-associated IGFBP-3 on PTC surfac es, without changes in IGF-I receptor numbers or affinity and without changes in PTC mRNA for IGFBP-3. Des(1-3)IGF-I, an analog that binds t o the IGF-I receptor but not to IGFBPs, provided a less potent stimulu s for PTC growth compared with IGF-I, indicating that cell-associated IGFBP-3 facilitates the action of IGF-I on PTC. The results support im portant paracrine roles for both IGF-I and IGFBPs in the interstitial regulation of proximal tubule growth and transport.