CYCLOSPORINE STIMULATES EXPRESSION OF TRANSFORMING GROWTH FACTOR-β IN RENAL CELLS POSSIBLE MECHANISM OF CYCLOSPORINES ANTIPROLIFERATIVE EFFECTS

Abstract

CsA induces a reversible inhibition of proliferation in cultured murine proximal tubular cells (MCT cells) and syngeneic tubulointerstitial fibroblasts (TFB). To test whether this effect may be caused by endogenous synthesis and release of transforming growth factor-beta 1 (TGF-beta 1), a well-known inhibitor of mitosis, MCT cells and TFB grown in serum-free media were treated with different concentrations of CsA. CsA, in a dose-dependent manner in a range of 500-2000 ng/ml, stimulated expression of TGF-beta 1 protein and steady-state mRNA levels in both cell lines (MCT cells: controls, 9.3 +/- 1.0; 1500 ng/ml CsA, 19.1 +/- 6.1 pg TGF-beta 1/10(3) cells [P < 0.05 vs. controls]; TFB: controls, 5.4 +/- 0.9; 1500 ng/ml CsA, 7.7 +/- 0.3 pg TGF-beta 1/10(3) cells; n = 6). Short-term daily intraperitoneal injections of CsA (40 mg/kg body weight/day) into SJL mice for 1 and 4 weeks also induced an increase in whole kidney levels of TGF-beta 1 mRNA. Incubation of MCT cells and TFB with CsA in the presence of 30 micrograms/ml of a neutralizing anti-TGF-beta 1-3 mAb partly reversed the cell cycle arrest induced by CsA. These data suggest that CsA-mediated intrarenal synthesis and release of TGF-beta 1 may play a role in the CsA-induced growth arrest and might therefore be relevant in the development of chronic CsA nephrotoxicity, which is characterized by striped fibrosis and tubular atrophy.