Nephrol Dial Transplant (2002) 17: 1568-1577
© 2002 European Renal Association-European Dialysis and Transplant Association
Cyclosporine A up-regulates the expression of TGF-ß1 and its receptors type I and type II in rat mesangial cells
Department of Internal Medicine–Nephrology, University Hospital Charité, Campus Charité Mitte, Humboldt-University, Berlin, Germany
Background. Chronic cyclosporine A (CsA) nephropathy is a well described side effect of CsA treatment. CsA has been shown to induce the synthesis of extracellular matrix (ECM) proteins in mesangial cells (MCs) in vitro, and glomerulosclerosis in vivo. Transforming growth factor-ß1 (TGF-ß1) is a potent stimulus for the synthesis of ECM proteins in MCs. We investigated whether CsA up-regulates the expression of TGF-ß1 and its receptors type I (TßR-I) and type II (TßR-II) in cultured rat MCs, and whether this effect translates into enhanced matrix protein accumulation.
Methods. Resting MCs were incubated in the presence or absence of CsA and anti-TGF-ß1 antibodies. Time- and concentration-dependent expression of TGF-ß1, TßR-I and TßR-II were measured at both the mRNA (competitive reverse transcription PCR) and protein level (enzyme-linked immunosorbent assay (ELISA) and western blotting). Fibronectin (FN) and plasminogen activator inhibitor type-1 (PAI-1) synthesis were measured by ELISA.
Results. Compared with untreated controls, CsA stimulated mRNA production of TGF-ß1 (maximum at 72 h, 500 ng/ml CsA: 2.1±0.5-fold, P<0.001) and TßR-II (maximum at 72 h, 1000 ng/ml CsA: 2.4±0.4-fold, P<0.005) time- and dose-dependently. TßR-I mRNA concentrations remained unchanged. Protein concentrations were analysed at 96 h: TGF-ß1, 220±32 vs 86±24 pg/ml, P<0.001 (500 ng/ml CsA vs control); TßR-I, 2.0±0.5-fold, P<0.005 (1000 ng/ml CsA vs control); TßR-II, 2.5±0.7-fold, P<0.05 (1000 ng/ml CsA vs control). CsA (500 ng/ml) also enhanced the production of FN (1.6-fold, P<0.05) and PAI-1 (2.0-fold, P<0.05). Co-incubation with neutralizing anti-TGF-ß1 antibodies reduced (P<0.05) CsA-induced expression of TßR-I (1.0±0.1-fold), TßR-II (1.3±0.1-fold) and PAI-1 (1.3-fold), but not FN production (1.6-fold).
Conclusions. Pharmacologically relevant concentrations of CsA time- and dose-dependently up-regulate the expression of TGF-ß1 and, via autocrine mechanisms, its receptors type I and II in rat MCs. Whereas up-regulation of PAI-1 is mediated by TGF-ß1, up-regulation of FN is—at least in part—either directly induced by CsA or mediated by factors other than TGF-ß1.
Keywords: cyclosporine A; glomerulosclerosis; mesangial cells; TGF-ß
Correspondence and offprint requests to: Dr Johannes Waiser, Medizinische Klinik mit Schwerpunkt Nephrologie, Universitätsklinikum Charité, Campus Charité Mitte, Schumannstrasse 20/21, 10117 Berlin, Germany. Email: johannes.waiser{at}charite.de
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