Fibrogenic effects of cyclosporin A on the tubulointerstitium: Role of cytokines and growth factors

The clinical utility of cyclosporin A (CyA) as an immunosuppressive agent h as been significantly limited by the frequent occurrence of chronic nephrot oxicity, characterised by tubular atrophy, interstitial fibrosis and progre ssive renal impairment. The pathogenesis of this condition remains poorly u nderstood, but has been postulated to be due to either direct cytotoxicity or indirect injury secondary to chronic renal vasoconstriction, Using prima ry cultures of human proximal tubule cells (PTCs) and renal cortical fibrob lasts (CFs) as an in vitro model of the tubulointerstitium, we have been ab le to demonstrate that clinically relevant concentrations of CyA are direct ly toxic to these cells and promote fibrogenesis by a combination of suppre ssed matrix metalloproteinase activity and augmented fibroblast collagen sy nthesis. The latter effect occurs secondary to the ability of CyA to stimul ate autocrine secretion of insulin-like growth factor-1 by CFs and paracrin e secretion of transforming growth facror-beta(1) by PTCs. Many of these pr ofibrotic mechanisms are completely reversed by concurrent administration o f the angiotensin-converting enzyme inhibitor, enalaprilat, which has prove n efficacy in preventing chronic CyA nephropathy in vivo. These studies hig hlight the unique potential that human renal cell cultures offer for studyi ng the role of local cytokine networks in tubulointerstitial disease and fo r developing more effective treatment strategies which specifically target fibrogenic growth factor activity following nephrotoxic injuries. Copyright (C) 1999 S. Karger AG, Basel.