2-methylquinazoline derivative F7 as a potent and selective HDAC6 inhibitor protected against rhabdomyolysis-induced acute kidney injury


Autoři: Jing Liu aff001;  Xue Cui aff002;  Fan Guo aff001;  Xinrui Li aff001;  Lingzhi Li aff001;  Jing Pan aff001;  Sibei Tao aff001;  Rongshuang Huang aff001;  Yanhuan Feng aff001;  Liang Ma aff001;  Ping Fu aff001
Působiště autorů: Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China aff001;  State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China aff002
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224158

Souhrn

Histone deacetylases 6 (HDAC6) has been reported to be involved in the pathogenesis of rhabdomyolysis-induced acute kidney injury (AKI). Selective inhibition of HDAC6 activity might be a potential treatment for AKI. In our lab, N-hydroxy-6-(4-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)nicotinamide (F7) has been synthesized and inhibited HDAC6 activity with the IC50 of 5.8 nM. However, whether F7 possessed favorable renoprotection against rhabdomyolysis-induced AKI and the involved mechanisms remained unclear. In the study, glycerol-injected mice developed severe AKI symptoms as indicated by acute renal dysfunction and pathological changes, accompanied by the overexpression of HDAC6 in tubular epithelial cells. Pretreatment with F7 at a dose of 40 mg/kg/d for 3 days significantly attenuated serum creatinine, serum urea, renal tubular damage and suppressed renal inflammatory responses. Mechanistically, F7 enhanced the acetylation of histone H3 and α-tubulin to reduce HDAC6 activity. Glycerol-induced AKI triggered multiple signal mediators of NF-κB pathway as well as the elevation of ERK1/2 protein and p38 phosphorylation. Glycerol also induced the high expression of proinflammatory cytokine IL-1β and IL-6 in kidney and human renal proximal tubule HK-2 cells. Treatment of F7 notably improved above-mentioned inflammatory responses in the injured kidney tissue and HK-2 cell. Overall, these data highlighted that 2-methylquinazoline derivative F7 inhibited renal HDAC6 activity and inflammatory responses to protect against rhabdomyolysis-induced AKI.

Klíčová slova:

Apoptosis – Cytokines – Glycerol – Histones – Inflammation – Kidneys – Phosphorylation – Urea


Zdroje

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2019 Číslo 10