Loss of α(E)‐catenin‐Fscn2 signaling Increases Cisplatin‐Induced Apoptosis in Aged Kidney

Abstract

Aging patients are highly susceptible to acute kidney injury. Previous studies in our laboratory demonstrated a dramatic decrease of α(E)‐catenin expression in proximal tubular epithelium in the aged kidney. We created stable α(E)‐catenin knock‐down NRK‐52E (C2) cells (NT3 is the non‐targeted control) and observed a significant loss of viability in C2 cells as compared with NT3 cells after cisplatin challenge. In this study, we aimed to delineate the pathway by which loss of α(E)‐catenin increases cisplatin injury. Increased caspase‐8 and ‐9 activation and cytosolic cytochrome C were observed in C2 cells after cisplatin treatment. Blocking apoptosis, using caspase‐8 or ‐9 inhibitors, completely abolishes the increased susceptibility of C2 cells. Interestingly, the expression of fascin actin bundling protein 2 (Fscn2) is decreased in α(E)‐catenin knock‐down cells. Re‐expression of Fscn2 in C2 cells attenuates the increased apoptosis following cisplatin challenge. Furthermore, our in vivo study showed a significant increase in serum creatinine, KIM‐1 and in situ apoptosis levels at 72 hr after a single dose of cisplatin in 24‐month‐old rats, but not in 4‐month‐old rats. The expression of Fscn2 was also decreased in aged kidney. Taken together, these results suggest that loss of α(E)‐catenin‐Fscn2 signaling increases cisplatin‐induced apoptosis in aged kidney.