In vitro effects of simvastatin on human tubulointerstitial cells and cyclosporin nephrotoxicity. Johnson, David W, Heather J Saunders, Michael J Field, Carol A Pollock. Department of Medicine, University of Sydney, Sydney, Australia 2006.
APStracts 5:0187F, 1998.
To investigate the possibility that 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors ameliorate renal disease via direct effects on the tubulointerstitium, primary cultures of human proximal tubule cells (PTC) and renal cortical fibroblasts (CF) were exposed for 24 hours to simvastatin (0.1 - 10 ?mol/L) under basal conditions and in the presence of 1000 ng/ml of cyclosporin (CyA), which we have previously shown to promote in vitro interstitial matrix accumulation at least partially via activation of local cytokine networks. Simvastatin, in micromolar concentrations, engendered cholesterol-independent inhibition of CF and PTC thymidine incorporation and cholesterol-dependent suppression of PTC apical sodium-hydrogen exchange (NHE) (ethylisopropylamiloride-sensitive apical 22Na+ uptake). Similarly, CF secretion of insulin-like growth factor-I (IGF-I) and IGF binding protein-3 were depressed, whilst CF collagen synthesis ([3H]proline incorporation) and PTC secretion of the fibrogenic cytokines, transforming growth factor-(1 and platelet -derived growth factor, were unaffected. A lower concentration (0.1 ?mol/L) of simvastatin did not affect any of the above parameters under basal conditions, but completely prevented CyA-stimulated CF collagen synthesis (control 6.6(0.6%, CyA 8.3?0.6%, CyA+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/day, respectively, p<0.05). The results suggest that simvastatin exerts direct cholesterol-dependent and -independent effects on the human kidney tubulointerstitium. HMGCoA reductase inhibitors may ameliorate interstitial fibrosis complicating CyA therapy via direct actions on human renal cortical fibroblasts. 

Received 18 May 1998; accepted in final form 13 October 1998.
APS Manuscript Number F124-8.
Article publication pending Am. J. Physiol. (Renal Physiology).
ISSN 1080-4757 Copyright 1998 The American Physiological Society.
Published in APStracts on 10 November 1998