| Titel: | Il-18 Mediates Proapoptotic Signaling in Renal Tubular Cells through a Fas Ligand-Dependent Mechanism |
|---|---|
| Autor: | Zhang, H. J. Hile, K. L. Asanuma, H. Vanderbrink, B. Franke, E. I. Campbell, M. T. Meldrum, K. K. |
| Mediengruppe: | journal article |
| Herausgeber: | --- |
| Zeitschrift: | American Journal of Physiology-Renal Physiology |
| Jahr: | 2011 |
| Band: | 301 |
| Heft: | 1 |
| Seiten: | F171-F178 |
| Sprache: | English |
| Abstract: | Zhang H, Hile KL, Asanuma H, Vanderbrink B, Franke EI, Campbell MT, Meldrum KK. IL-18 mediates proapoptotic signaling in renal tubular cells through a Fas ligand-dependent mechanism. Am J Physiol Renal Physiol 301: F171-F178, 2011. First published April 20, 2011; doi: 10.1152/ajprenal.00339.2010.-Renal tubular cell apoptosis is a significant component of obstruction-induced renal injury, and it results in a progressive loss in renal parenchymal mass during renal obstruction. Although IL-18 is an important mediator of inflammatory renal disease and renal fibrosis, its role in obstruction-induced renal tubular cell apoptosis remains unclear. To study this, male C57BL6 wild-type mice and C57BL6 mice transgenic for human IL-18-binding protein (IL-18BP Tg) were subjected to renal obstruction vs. sham operation. The kidneys were harvested after 1 or 2 wk and analyzed for IL-18 production, apoptosis, caspase activity, and Fas/Fas Ligand (FasL) expression. HK-2 cells were similarly analyzed for apoptosis and proapoptotic signaling following 3 days of direct exposure to IL-18 vs. control media. Renal obstruction induced a significant increase in IL-18 production, renal tubular cell apoptosis, caspase activation, and FasL expression. IL-18 neutralization, on the other hand, significantly reduced obstruction-induced apoptosis, caspase-8 and caspase-3 activity, and FasL expression. In vitro experiments similarly demonstrate that IL-18 stimulation induces apoptosis, FasL expression, and increases active caspase-8 and caspase-3 expression in a dose-dependent fashion. siRNA knockdown of FasL gene expression, however, significantly reduced IL-18-induced apoptosis. This study reveals that IL-18 is a significant mediator of obstruction-induced tubular cell apoptosis, and it demonstrates that IL-18 stimulates proapoptotic signaling through a FasL-dependent mechanism. |