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.
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The authors contributed the following to the work: experiments (Xinhui Wang), manuscript preparation (Xinhui Wang, Alan R. Parrish). Research reported in this publication was supported by the National Institute of Aging of the National Institutes of Health under award number RO1AG034154. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
This study was funded by the National Institute of Aging of the National Institutes of Health under award number RO1AG034154.
Conflict of Interest
The authors declare that they have no conflicts of interest.
Human and Animal Rights and Informed Consent
All animal experiments and care were approved by the University of Missouri Animal Care and Use Committee in accordance with the National Institutes of Health (NIH). This article does not contain studies with human participants.
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Wang, X., Parrish, A.R. Loss of α(E)-catenin promotes Fas mediated apoptosis in tubular epithelial cells. Apoptosis 20, 921–929 (2015). https://doi.org/10.1007/s10495-015-1129-x