REGULATION OF FAS AND FAS LIGAND EXPRESSION IN CULTURED MURINE RENAL-CELLS AND IN THE KIDNEY DURING ENDOTOXEMIA

Fas ligand (Fast) and Fas belong to a recently described family of cyt okines and receptors with similarities to tumor necrosis factor (TNF) and its receptors. Upon engagement by specific antibodies or by Fast, Fas transduces a signal for apoptosis in permissive cells. Although ap optosis occurs during renal development and following injury to mature cells, the factors responsible for programmed renal cell death are un certain. We have studied Fas expression by renal cells in vitro and du ring endotoxemia in mice. Several renal cell types, including glomerul ar mesangial cells and tubular epithelial cells express a Fas transcri pt in culture. Lipopolysaccharides (LPS), interleukin-1 beta, interfer on-gamma (IFN-gamma), and TNF-alpha increase the levels of Fas mRNA in cultured mesangial and tubular cells. TNF-alpha and LPS raise the lev el of Fas mRNA in a time- and dose-dependent manner with Fas receptor expression peaking after 72 h of exposure to LPS. Anti-Fas antibodies can induce the death of cultured mesangial cells. This cell. death sho ws the characteristic changes of apoptosis, including DNA fragmentatio n and pyknotic changes of the nucleus. Increases in Fas by LPS, TNF-al pha, and IFN-gamma enhance the killing induced by the anti-Fas antibod y. Fast is also expressed by cultured renal cells, and TNF-alpha treat ment of mesangial cells increases its expression. In vivo, Fas mRNA is present at low level in normal kidney. LPS increases the levels of Fa s mRNA and protein in kidney and produces evidence of apoptosis along nephrons. These data suggest that transcripts encoding natural Fast an d Fas are induced by LPS and may play a role in endotoxemia-induced ac ute renal failure and organ dysfunction.