HDAC6 Inhibition Alleviates Ischemia- and Cisplatin-Induced Acute Kidney Injury by Promoting Autophagy

Histone deacetylase (HDAC) 6 exists exclusively in cytoplasm and deacetylates cytoplasmic proteins such as alpha-tubulin. HDAC6 dysfunction is associated with several pathological conditions in renal disorders, including UUO-induced fibrotic kidneys and rhabdomyolysis-induced nephropathy. However, the role of HDAC6 in ischemic acute kidney injury (AKI) and the mechanism by which HDAC6 inhibition protects tubular cells after AKI remain unclear. In the present study, we observed that HDAC6 was markedly activated in kidneys subjected to ischemia- and cisplatin (cis)-induced AKI treatment. Pharmacological inhibition of HDAC6 alleviated renal impairment and renal tubular damage after ischemia and cisplatin treatment. HDAC6 dysfunction was associated with decreased acetylation of alpha-tubulin at the residue of lysine 40 and autophagy. HDAC6 inhibition preserved acetyl-alpha-tubulin-enhanced autophagy flux in AKI and cultured tubular cells. Genetic ablation of the renal tubular (RT) Atg7 gene or pharmacological inhibition of autophagy suppressed the protective effects of HDAC6. Taken together, our study indicates that HDAC6 contributes to ischemia- and cisplatin-induced AKI by inhibiting autophagy and the acetylation of alpha-tubulin. These results suggest that HDAC6 could be a potential target for ischemic and nephrotoxic AKI.

Automated summary

HDAC6 plays an important role in ischemic and nephrotoxic acute kidney injury (AKI) by inhibiting autophagy and the acetylation of alpha-tubulin. Inhibition of HDAC6 protects tubular cells from AKI-induced damage.