title: Loss of α(E)-catenin promotes Fas mediated apoptosis in tubular epithelial cells.
abstract: The aging kidney undergoes structural and functional alterations which make it more susceptible to drug-induced acute kidney injury (AKI). Previous studies in our lab have shown that the expression of α(E)-catenin is decreased in aged kidney and loss of α(E)-catenin potentiates AKI-induced apoptosis, but not necrosis, in renal tubular epithelial cells (NRK-52E cells). However, the specific apoptotic pathway underlying the increased AKI-induced cell death is not yet understood. In this study, cells were challenged with nephrotoxicant cisplatin to induce AKI. A ~5.5-fold increase in Fas expression in C2 (stable α(E)-catenin knockdown) relative to NT3 (non-targeted control) cells was seen. Increased caspase-8 and -9 activation was induced by cisplatin in C2 as compared to NT3 cells. In addition, decreased Bcl-2 expression and increased BID cleavage and cytochrome C release were detected in C2 cells after cisplatin challenge. Treating the cells with cisplatin, in combination with a Bcl-2 inhibitor, decreased the viability of NT3 cells to the same level as C2 cells after cisplatin. Furthermore, caspase-3/-7 activation is blocked by Fas, caspase-8, caspase-9 and pan-caspase inhibitors. These inhibitors also completely abolished the difference in viability between NT3 and C2 cells in response to cisplatin. These results demonstrate a Fas-mediated apoptotic signaling pathway that is enhanced by the age-dependent loss of α(E)-catenin in renal tubule epithelial cells.
authors.affiliation: Medical Pharmacology and Physiology, School of Medicine, University of Missouri, MA 415 Medical Sciences Building, One Hospital Drive, Columbia, MO, 65212, USA.
authors.forename: Xinhui
authors.initials: X
authors.lastname: Wang
authors.forename: Alan R
authors.initials: AR
authors.lastname: Parrish
mesh_terms: D058186:Acute Kidney Injury / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000819:agonists / Q000378:metabolism; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D011916:Rats, Inbred F344; D015398:Signal Transduction; D051178:alpha Catenin / Q000235:genetics*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D051178:alpha Catenin; D019014:fas Receptor; D002945:Cisplatin