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

Abstract

Histone deacetylase (HDAC) 6 exists exclusively in cytoplasm and deacetylates cytoplasmic proteins such as α-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 α-tubulin at the residue of lysine 40 and autophagy. HDAC6 inhibition preserved acetyl-α-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 α-tubulin. These results suggest that HDAC6 could be a potential target for ischemic and nephrotoxic AKI.

Histone deacetylase‐mediated silencing of PSTPIP2 expression contributes to aristolochic acid nephropathy‐induced PANoptosis

“…Kidneys are rich in acetylated lysine proteins and express many of the acetyltransferases and deacetylases in the nephron (Shi et al, 2022) and HDAC participates in the pathogenesis of acute kidney injury by removing acetyl groups from histones and non‐histones (Hyndman, 2020). To determine which isoforms of HDAC were induced in response to AAI treatment, kidney tissue was harvested at 24, 48 and 72 h after AAI administration.…”

Emerging significance and therapeutic targets of ferroptosis: a potential avenue for human kidney diseases

“…IRI consists of two stages: the first stage is hypoxia-ischemia, which is characterized by energy failure and cell death primarily caused by apoptosis; in the reperfusion stage, ROS are overproduced, and ferroptosis is induced [ 143 , 144 ]. Moreover, autophagy occurs in human renal tubular epithelial cells during both pathological processes [ 145 , 146 ]. In summary, the main mechanisms of ferroptosis during IRI are excessive ROS production, cascade-amplified inflammatory reactions and ferritinophagy.…”