In vitro effects of simvastatin on tubulointerstitial cells in a human model of cyclosporin nephrotoxicity

To investigate the possibility that 3-hydroxy-3-methylglutaryl CoA (HMGCoA) reductase inhibitors ameliorate renal disease via direct effects on the tu bulointerstitium, primary cultures of human proximal tubule cells (PTC) and renal cortical fibroblasts (CF) were exposed for 24 h to simvastatin (0.1- 10 mu mol/l) under basal conditions and in the presence of 1,000 ng/ml of c yclosporin (CsA), which we have previously shown to promote in vitro inters titial matrix accumulation at least partially via activation of local cytok ine networks. Simvastatin, in micromolar concentrations, engendered cholest erol-independent inhibition of CF and PTC thymidine incorporation and chole sterol-dependent suppression of PTC apical Na+/H+ exchange (NHE) (ethylisop ropyl-amiloride-sensitive apical Na-22(+) uptake). Similarly, CF secretion of insulin-like growth factor-I (IGF-I) and IGF binding protein-3 were depr essed, whereas CF collagen synthesis ([H-3]proline incorporation) and PTC s ecretion of the fibrogenic cytokines, transforming growth factor-beta 1, an d platelet-derived growth factor were unaffected. A lower concentration (0. 1 mu mol/l) of simvastatin did not affect any of the above parameters under basal conditions but completely prevented CsA-stimulated CF collagen synth esis (control, 6.6 +/- 0.6; kCsA, 8.3 +/- 0.6; CsA+simvastatin, 6.2 +/- 0.5 %; P < 0.05) and IGF-I secretion (89.5 +/- 16.6, 204.7 +/- 57.0, and 94.6 /- 22.3 ng mg protein-l day-l, respectively; P < 0.05). The results suggest that simvastatin exerts direct cholesterol-dependent and -independent effe cts on the human kidney tubulointerstitium. HMGCoA reductase inhibitors may ameliorate interstitial fibrosis complicating CsA therapy via direct actio ns on human renal cortical fibroblasts.