Involvement of Fas-dependent apoptosis in renal tubular epithelial cell deletion in chronic renal failure

Renal tubular atrophy predicts a poor prognosis in chronic renal failure, b ut the molecular mechanisms that regulate tubular atrophy are unknown. Beca use the Fas apoptosis pathway has been implicated in disease pathogenesis a nd Fas is expressed in kidney, we hypothesized that Fas-mediated renal tubu le epithelial cell (RTC) apoptosis contributes to tubular atrophy in chroni c renal failure. Immunohistochemical analyses of renal sections from two mu rine models of progressive renal disease revealed increases in RTC Fas expr ession and apoptosis compared with tissue sections from age-matched control kidneys. Increased RTC apoptosis was not accompanied by compensatory hyper plasia, suggesting that RTCs targeted for Fas-dependent apoptotic deletion contribute to tubular atrophy. These data are supported by in vitro studies that showed that interleukin-1 alpha or tumor necrosis factor-alpha, cytok ines that are secreted in chronic renal failure, stimulated increases in Fa s expression in cultured RTCs. Both murine kidney cortex and RTCs in cultur e demonstrated constitutive expression of Fas ligand, a feature that is cha racteristically restricted to lymphocytes and immune-privileged tissues and previously unrecognized in RTCs. Functional studies revealed that interleu kin-1 alpha-stimulated RTC Fas expression was accompanied by increased apop tosis, which was inhibited by blocking anti-Fas ligand antibodies. The data suggest that up-regulated RTC Fas binds to Fas ligand on adjacent RTCs, wh ich then leads to RTC death by fratricide. We propose this pathway as an in itiating mechanism of tubular atrophy.