Cyclosporin exerts a direct fibrogenic effect on human tubulointerstitial cells: Roles of insulin-like growth factor I, transforming growth factor beta(1), and platelet-derived growth factor

To assess the direct fibrogenic effects of cyclosporin A (CyA) on the human tubulointerstitium, primary cultures of human renal proximal tubule cells (PTC) and renal cortical fibroblasts (CF) were incubated for 24 h with vari ous concentrations of CyA. Cytotoxicity was confirmed in both cell populati ons by dose-dependent inhibition of thymidine incorporation, viability, and PTC apical sodium-hydrogen exchange activity (ethylisopropylamiloride-sens itive apical Na-22(+) uptake). Compared with controls, both 500 and 1000 ng /ml CyA significantly stimulated CF collagen synthesis (proline incorporati on 4.6 +/- 0.4, 6.5 +/- 0.8, and 7.1 +/- 1.0%, respectively; p <.05) and in hibited matrix metalloproteinase-2 (100%, 85.7 +/- 10.0%, and 38.8 +/- 9.2% ) and matrix metalloproteinase-9 activity (100%, 110.6 +/- 19.0%, and 49.9 +/- 12.8%), CyA did not affect CF secretion of transforming growth factor b eta(1), but markedly stimulated insulin-like growth factor-I (IGF-I) secret ion and inhibited secretion of both IGF-I binding protein-(IGFBP)-3 and IGF BP-2, CyA-induced CF collagen synthesis was abrogated by 5 mu g/ml anti-IGF -I receptor antibody, but not by 5 mu g/ml murine nonimmune globulin. Incre asing concentrations of CyA progressively augmented PTC secretion of the fi brogenic cytokines transforming growth factor-beta(1) and platelet-derived growth factor. These results indicate that clinically relevant concentratio ns of CyA are directly toxic to PTC and CF, irrespective of hemodynamic eff ects, and promote interstitial fibrosis by inhibiting matrix degradation an d stimulating cortical fibroblast collagen synthesis via induction of autoc rine IGF-I action. The latter effect may be further accentuated by the abil ity of CyA to augment secretion of transforming growth factor beta(1) and p latelet-derived growth factor by PTCs.