Low-density lipoproteins enhance transforming growth factor-beta 1 (TGF-beta 1) and monocyte chemotactic protein-1 (MCP-1) expression induced by cyclosporin in human mesangial cells

Cyclosporin (CsA) is widely used in the treatment of renal disease and tran splantation, which are often complicated by alterations of lipid metabolism . Both chronic administration of CsA and hyperlipidaemia have been shown to evoke an early macrophage influx and have progressively led to glomerular and interstitial sclerosis. MCP-1 is the major monocyte chemoattractant sec reted by stimulated mesangial cells and TGF-beta 1 is a key mediator of fib rogenesis in chronic progressive renal fibrosis. Thus, the combined effect of CsA and low-density lipoprotein (LDL) on the gene and protein expression of MCP-1 and TGF-beta 1 in cultured human mesangial cells (HMC) was explor ed. Both agents induced an early and persistent increase of MCP-1 and TGF-b eta 1 mRNA levels and protein release. The simultaneous addition of CsA and LDL did not display any additive effect on target gene expression, but it caused a synergistic effect on MCP-1 and TGF-beta 1 protein secretion into culture medium. On the other hand, CsA and LDL had different effects on cel l proliferation: the latter increased DNA synthesis, whereas CsA inhibited both spontaneous and mitogen-stimulated mesangial cell growth. The study co ncludes that CsA and LDL display an additive effect on TGF-beta 1 and MCP-1 synthesis and release by HMC, thus possibly co-operating to induce an earl y macrophage influx and the subsequent mesangial expansion and increased ex tracellular matrix deposition. However, in contrast they seem to modulate H MC proliferation differently, which is a further critical event intimately involved in the development of glomerulosclerosis.