title: Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury.
abstract: Histone deacetylase 6 (HDAC6) inhibition has been reported to protect against ischemic stroke and prolong survival after sepsis in animal models. However, it remains unknown whether HDAC6 inhibition offers a renoprotective effect after acute kidney injury (AKI). In this study, we examined the effect of tubastatin A (TA), a highly selective inhibitor of HDAC6, on AKI in a murine model of glycerol (GL) injection-induced rhabdomyolysis. Following GL injection, the mice developed severe acute tubular injury as indicated by renal dysfunction; expression of neutrophil gelatinase-associated lipocalin (NGAL), an injury marker of renal tubules; and an increase of TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells. These changes were companied by increased HDAC6 expression in the cytoplasm of renal tubular cells. Administration of TA significantly reduced serum creatinine and blood urea nitrogen levels as well as attenuated renal tubular damage in injured kidneys. HDAC6 inhibition also resulted in decreased expression of NGAL, reduced apoptotic cell, and inactivated caspase-3 in the kidney after acute injury. Moreover, injury to the kidney increased phosphorylation of nuclear factor (NF)-κB and expression of multiple cytokines/chemokines including tumor necrotic factor-α and interleukin-6 and monocyte chemoattractant protein-1, as well as macrophage infiltration. Treatment with TA attenuated all those responses. Finally, HDAC6 inhibition reduced the level of oxidative stress by suppressing malondialdehyde (MDA) and preserving expression of superoxide dismutase (SOD) in the injured kidney. Collectively, these data indicate that HDAC6 contributes to the pathogenesis of rhabdomyolysis-induced AKI and suggest that HDAC6 inhibitors have therapeutic potential for AKI treatment.
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Yingfeng
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Liuqing
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Fang
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Shuchen
authors.initials: S
authors.lastname: Ma
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Ma
authors.affiliation: School of Life Sciences and Technology, Tongji University, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Nie
authors.affiliation: Department of Internal Medicine, Pudong New District Gongli Hospital, Shanghai, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Pi
authors.affiliation: School of Life Sciences and Technology, Advanced Institute of Translational Medicine, Tongji University, Shanghai, China; and.
authors.forename: Andong
authors.initials: A
authors.lastname: Qiu
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.|Department of Medicine, Rhode Island Hospital and Brown University School of Medicine, Providence, Rhode Island.
authors.forename: Shougang
authors.initials: S
authors.lastname: Zhuang
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; naliubrown@163.com.
authors.forename: Na
authors.initials: N
authors.lastname: Liu
mesh_terms: D000107:Acetylation; D058186:Acute Kidney Injury / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers / Q000097:blood; D001806:Blood Urea Nitrogen; D053148:Caspase 3 / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D019610:Cytoprotection; D004195:Disease Models, Animal; D005990:Glycerol; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D000071068:Lipocalin-2 / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D012206:Rhabdomyolysis / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D015398:Signal Transduction / Q000187:drug effects; D054875:Ubiquitination
chemical_list: D015415:Biomarkers; D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D018836:Inflammation Mediators; D000071068:Lipocalin-2; D016328:NF-kappa B; C071332:Lcn2 protein, mouse; C553587:tubastatin A; D003404:Creatinine; C505409:Casp3 protein, mouse; D053148:Caspase 3; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D005990:Glycerol
keywords: HDAC6; acute kidney injury; inflammation; oxidative stress; rhabdomyolysis