Loss of alpha(E)‐catenin increases cisplatin nephrotoxicity (691.2)

Abstract

Cisplatin is one of the most potent and widely used antineoplastic drugs. However, the use of cisplatin is dramatically limited by its side effect, nephrotoxicity. Evidence has shown that there is an increased incidence and severity of acute kidney injury (AKI) in the elderly. We previously reported a dramatic decrease of α‐catenin expression in proximal tubular epithelium of aged kidney. We hypothesize that loss of α(E)‐catenin increases susceptibility to cisplatin. To study the effects of reduced α‐catenin, shRNA knock‐down of α(E)‐catenin (C2) was generated in NRK‐52E cells; NT3 is the non‐targeted control. Confluent cultures of cells were challenged with cisplatin (50, 100, 150 μM) for 24 hr and C2 cells exhibited a significant loss of viability at all concentrations as compared with NT3 cells. Interestingly, the expression of α(E)‐catenin was further decreased in both cell lines. Importantly, higher caspase 3/7 activity was observed in C2 cells than NT3 cells after cisplatin treatment indicating the increased susceptibility may be due to apoptosis. To elucidate the mechanism of increased apoptosis in C2 cells, we performed RNA sequencing and identified that CYFIP2, a pro‐apoptotic gene, had 6.44 fold higher expression in C2 cells than NT3 cells. This finding was confirmed by qPCR. Taken together, these results suggest that loss of α(E)‐catenin may increase cisplatin‐induced nephrotoxicity via apoptosis.Grant Funding Source: Supported by NIH RO1AAG034154