Abstract
Histone deacetylase 6 (HDAC6) contributed to the pathogenesis of rhabdomyolysis-induced acute kidney injury (AKI) and selective inhibition of HDAC6 activity may be a promising strategy for the treatment of AKI. Compound 23BB as a highly selective HDAC6 inhibitor was designed, synthesized by our lab and exhibited therapeutic potential in various cancer models with good safety. However, it remained unknown whether 23BB as a drug candidate could offer renal protective effect against rhabdomyolysis-induced AKI. In the present study, we investigated the effect of 23BB in a murine model of glycerol (GL) injection-induced rhabdomyolysis. Following GL injection, the mice developed severe AKI as indicated by acute renal dysfunction and histologic changes, accompanied by increased HDAC6 expression in the cytoplasm of tubular epithelial cells. Pharmacological inhibition of HDAC6 by 23BB pretreatment significantly reduced serum creatinine and serum blood urea nitrogen (BUN) levels as well as attenuated renal tubular damage in GL-injured kidneys. HDAC6 inhibition also resulted in reduced TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells, suppressed BAX, BAK, cleaved caspase-3 levels, and preserved Bcl-2 expression, indicating that 23BB exerted potent renoprotective effects by the regulation of tubular cell apoptosis. Moreover, GL-induced kidney injury triggered multiple signal mediators of endoplasmic reticulum (ER) stress including GRP78, CHOP, IRE1α, p-eIF2α, ATF4, XBP1, p-JNK, and caspase-12. Oral administration of 23BB improved above-mentioned responses in injured kidney tissues and suggested that 23BB modulated tubular cell apoptosis via the inactivation of ER stress. Overall, these data highlighted that renal protection of novel HDAC6 inhibitor 23BB is substantiated by the reduction of ER stress-mediated apoptosis in tubular epithelial cells of rhabdomyolysis-induced AKI.
Highlights
Acute kidney injury (AKI), characterized by a rapid decline of the glomerular filtration rate, is a serious clinical problem correlated with an aggressive disease course, high rates of mortality and increased risk of chronic kidney diseases (CKD) (Venkatachalam et al, 2015)
To determine whether 23BB may have a renal protective effect by targeting Histone deacetylase 6 (HDAC6), we examined the renal function and FIGURE 3 | 23BB inhibits the expression of HDAC6 and enhances the acetylation of histone H3. (A) The kidney tissue lysates were subjected to immunoblot analysis with indicated antibodies against HDAC6 and acetylated histone H3. (B) Expressions of HDAC6 and acetylated histone H3 were quantified by densitometry and normalized with β-actin
We found that pharmacological inhibition of HDAC6 by 23BB improved acute renal dysfunction indicated by reduced Serum creatinine (sCr) and blood urea nitrogen (BUN) levels in a GL-induced acute kidney injury (AKI) model
Summary
Acute kidney injury (AKI), characterized by a rapid decline of the glomerular filtration rate, is a serious clinical problem correlated with an aggressive disease course, high rates of mortality and increased risk of chronic kidney diseases (CKD) (Venkatachalam et al, 2015). The detailed mechanisms have not been fully comprehended, it has been well-established that endoplasmic reticulum (ER) stress-mediated apoptosis of tubular epithelium cells played crucial roles in rhabdomyolysis-induced AKI (Feng et al, 2016). The presence of misfolded proteins and other stresses lead to the activation of an adaptive program by the ER, known as the unfolded protein response (UPR), to restore protein-folding homeostasis (Walter and Ron, 2011). Initiation of the canonical UPR engages three distinct signaling branches, which are mediated by pancreatic ER kinase (PERK), activating transcription factor-6 (ATF6) and inositol-requiring transmembrane kinase/endonuclease-1 (IRE-1) (Gardner and Walter, 2011; Wang and Kaufman, 2016). The UPR is linked to the activation of stress kinases such as the c-Jun N-terminal kinase (JNK) and splicing of X-box binding protein 1 (XBP1) (Calfon et al, 2002; Kim et al, 2006). The combined action of these pathways results in the inhibition of protein translation, stimulation of protein degradation and production of chaperone proteins, triggering either recovery of ER function or cell death (Kim et al, 2006)
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