Background: Although many mediators involved in the pathogenesis of fibrosis are known, its precise mechanism is still unknown. In vitro experiments may contribute to the recognition of cellular changes which also take place during fibrosis. Methods: Renal tubular epithelial cells (EPC), mesangial cells (MC) and glomerular endothelial cells (GEDC) as well as endothelial cells (EDC) and myofibroblasts (MF) from cattle were isolated to measure the proliferation and protein synthesis in the presence of individual and combined cytokines/growth factors in cell cultures. Results: Cytokines stimulating or permitting the proliferation of myofibroblast-like cells (MFLC) (MC and MF), caused damage of endothelial cells (EDC, GEDC), whereas EPC were stable. The proliferation of MFLC was strongly stimulated by PDGF-BB and bFGF and elevated more than twofold in the presence of interleukin 4 (IL-4), but IL-4 alone had no effect. Furthermore, the proliferation of transdifferentiated endothelial cells (TEC), obtained by incubation of EDC with TNFα and bFGF, was stimulated with both PDGF-BB/IL-4 and bFGF/IL-4 in the same way and proved to be stable with respect to TNFα. Conclusion: Interleukin 4 co-stimulates the PDGF-BB- and bFGF-mediated proliferation of MC, MF, and TEC. TNFα does not inhibit the proliferation of extracellular matrix-synthesizing cells, but has an inhibitory or even toxic effect on EDC and GEDC. It may be concluded that cytokines released in inflamed renal tissue influence tubulointerstitial cells in different ways, resulting in progressive tissue damage and fibrosis in which the EDC would be the most sensitive cells. Thus, we speculate that microvascular injury in these areas leads to ischemia and malnutrition of tubular EPC and may be responsible for ongoing tubular damage and resulting renal interstitial fibrosis.

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