Blockade of histone deacetylase 6 protects against cisplatin-induced acute kidney injury

In this study, we utilized a murine model of cisplatin-induced acute kidney injury (AKI) and a highly selective inhibitor of HDAC6, tubastatin A (TA), to assess the role of HDAC6 in nephrotoxicity and its associated mechanisms. Cisplatin-induced AKI was accompanied by increased expression and activation of HDAC6; blocking HDAC6 with TA lessened renal dysfunction, attenuated renal pathological changes, reduced expression of neutrophil gelatinase-associated lipocalin and Kim-1, and decreased tubular cell apoptosis. In cultured human epithelial cells, TA or HDAC6 siRNA treatment also inhibited cisplatin-induced apoptosis. Mechanistic studies demonstrated that cisplatin induced phosphorylation of AKT and loss of E-cadherin in the nephrotoxic kidney, and administration of TA enhanced AKT phosphorylation and preserved E-cadherin expression. HDAC6 inhibition also potentiated autophagy as evidenced by increased expression of Atg7, Beclin-1, and decreased renal oxidative stress as demonstrated by upregulation of superoxide dismutase activity and downregulation of malondialdehyde levels. Moreover, TA was effective in inhibiting NF-B phosphorylation and suppressing the expression of tumor necrosis factor-a and interleukin-6. Collectively, these data provide strong evidence that HDAC6 inhibition is protective against cisplatin-induced AKI and suggest that HDAC6 may be a potential therapeutic target for AKI treatment.

Source: Clinical Science - January 22, 2018 Category: Biomedical Science Authors: Tang, J., Shi, Y., Liu, N., Xu, L., Zang, X., Li, P., Zhang, J., Zheng, X., Qiu, A., Zhuang, S. Tags: PublishAheadOfPrint Source Type: research