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

Abstract

Renal tubular atrophy predicts a poor prognosis in chronic renal failure, but the molecular mechanisms that regulate tubular atrophy are unknown. Because the Fas apoptosis pathway has been implicated in disease pathogenesis and Fas is expressed in kidney, we hypothesized that Fas-mediated renal tubule epithelial cell (RTC) apoptosis contributes to tubular atrophy in chronic renal failure. Immunohistochemical analyses of renal sections from two murine models of progressive renal disease revealed increases in RTC Fas expression and apoptosis compared with tissue sections from age-matched control kidneys. Increased RTC apoptosis was not accompanied by compensatory hyperplasia, 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-1alpha or tumor necrosis factor-alpha, cytokines that are secreted in chronic renal failure, stimulated increases in Fas expression in cultured RTCs. Both murine kidney cortex and RTCs in culture demonstrated constitutive expression of Fas ligand, a feature that is characteristically restricted to lymphocytes and immune-privileged tissues and previously unrecognized in RTCs. Functional studies revealed that interleukin-1alpha-stimulated RTC Fas expression was accompanied by increased apoptosis, which was inhibited by blocking anti-Fas ligand antibodies. The data suggest that up-regulated RTC Fas binds to Fas ligand on adjacent RTCs, which then leads to RTC death by fratricide. We propose this pathway as an initiating mechanism of tubular atrophy.

Induction of Renal Tubular Cell Apoptosis in Focal Segmental Glomerulosclerosis

“…MDCK cells are known to possess mechanisms for endocytosis (32), and our results indicate for the first time that they do take up albumin. We used stringent morphologic criteria and three complementary assays (propidium iodide staining, TUNEL assay, and DNA laddering) to demonstrate that these distal/ collecting cells undergo a dose-dependent apoptotic cell death (Left) MDCK cells that were incubated with various doses of BSA as indicated (in mg/ml) for 72 h were subjected to DNA laddering assay.…”

“…This choice was based on previous observations that tubular epithelial cell apoptosis is a well-known feature of chronic renal failure itself, which could add a confounding variable to our analysis (32). We used stringent morphologic criteria and three complementary assays (propidium iodide staining, TUNEL assay, and Fas immunolocalization) for the detection of apoptosis in the biopsy samples in a double-blind manner.…”

“…Thus, activation of the initiator procaspase 8 usually results from signaling via death receptors such as Fas, which are integral membrane proteins that transduce apoptotic signals to downstream molecules such as FADD (35). This Fas-FADD-caspase 8 pathway has been implicated in the renal tubule cell apoptosis after ischemic injury (28), during endotoxemia (36), during transplant rejection (37), and in the tubular atrophy of chronic renal failure (32). However, activation of the initiator pro-caspase 9 is dependent on mitochondrial signaling pathways involving members of the Bcl-2 family such as Bax and Bak (38).…”

α-Melanocyte Stimulating Hormone (MSH) decreases cyclosporine A induced apoptosis in cultured human proximal tubular cells

“…This finding suggests that Fas system-mediated tubular cell apoptosis can also be the principal mechanism of apoptosis in tubular atrophy in chronic CsA nephrotoxicity (19).…”

“…The CsA concentrations (500-1,000 ng/mL) used in this study were to represent the approximate concentration range in in vivo kidney tissue, and thus a nephrotoxic in vitro model simulating clinical setting (26). Apoptosis, a genetically regulated form of cell death has been observed in various renal diseases, e.g., ischemia-reperfusion injury, transplant rejection (27,28) as well as other conditions characterized by progressive tubulointerstitial injury and glomerulosclerosis (19). In chronic CsA nephrotoxicity model, increased apoptosis of tubulointerstitial cells were also observed and it correlated with pathologic findings such as tubular atrophy and interstitial fibrosis (10,11).…”