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: https://doi.org/10.1371/journal.pone.0224158


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


1. Lameire NH, Bagga A, Cruz D, De Maeseneer J, Endre Z, Kellum JA, et al. Acute kidney injury: an increasing global concern. Lancet. 2013;382(9887):170–9. doi: 10.1016/S0140-6736(13)60647-9 23727171

2. Venkatachalam MA, Weinberg JM, Kriz W, Bidani AK. Failed Tubule Recovery, AKI-CKD Transition, and Kidney Disease Progression. J Am Soc Nephrol. 2015;26(8):1765–76. doi: 10.1681/ASN.2015010006 25810494

3. Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. N Engl J Med. 2009;361(1):62–72. doi: 10.1056/NEJMra0801327 19571284

4. Panizo N, Rubio-Navarro A, Amaro-Villalobos JM, Egido J, Moreno JA. Molecular Mechanisms and Novel Therapeutic Approaches to Rhabdomyolysis-Induced Acute Kidney Injury. Kidney Blood Press Res. 2015;40(5):520–32. doi: 10.1159/000368528 26512883

5. Komada T, Usui F, Kawashima A, Kimura H, Karasawa T, Inoue Y, et al. Role of NLRP3 Inflammasomes for Rhabdomyolysis-induced Acute Kidney Injury. Sci Rep. 2015;5:10901. doi: 10.1038/srep10901 26045078

6. Zager RA, Gamelin LM. Pathogenetic mechanisms in experimental hemoglobinuric acute renal failure. Am J Physiol. 1989;256(3 Pt 2):F446–55. doi: 10.1152/ajprenal.1989.256.3.F446 2923223

7. Chen GY, Nunez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010;10(12):826–37. doi: 10.1038/nri2873 21088683

8. Geng X, Wang Y, Hong Q, Yang J, Zheng W, Zhang G, et al. Differences in gene expression profiles and signaling pathways in rhabdomyolysis-induced acute kidney injury. Int J Clin Exp Pathol. 2015;8(11):14087–98. 26823722

9. Siddiqui RA, Simjee SU, Kabir N, Ateeq M, Shah MR, Hussain SS. N-(2-hydroxyphenyl)acetamide and its gold nanoparticle conjugation prevent glycerol-induced acute kidney injury by attenuating inflammation and oxidative injury in mice. Mol Cell Biochem. 2019;450(1–2):43–52. doi: 10.1007/s11010-018-3371-3 29790115

10. Zhang F, Lu S, Jin S, Chen K, Li J, Huang B, et al. Lidanpaidu prescription alleviates lipopolysaccharide-induced acute kidney injury by suppressing the NF-kappaB signaling pathway. Biomed Pharmacother. 2018;99:245–52. doi: 10.1016/j.biopha.2018.01.059 29334668

11. Zhang W, Kone BC. NF-kappaB inhibits transcription of the H(+)-K(+)-ATPase alpha(2)-subunit gene: role of histone deacetylases. Am J Physiol Renal Physiol. 2002;283(5):F904–11. doi: 10.1152/ajprenal.00156.2002 12372765

12. Guijarro C, Egido J. Transcription factor-kappa B (NF-kappa B) and renal disease. Kidney Int. 2001;59(2):415–24. doi: 10.1046/j.1523-1755.2001.059002415.x 11168923

13. Sen R, Baltimore D. Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell. 1986;47(6):921–8. doi: 10.1016/0092-8674(86)90807-x 3096580

14. de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. 2003;370(Pt 3):737–49. doi: 10.1042/BJ20021321 12429021

15. Boyault C, Sadoul K, Pabion M, Khochbin S. HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination. Oncogene. 2007;26(37):5468–76. doi: 10.1038/sj.onc.1210614 17694087

16. Feng Y, Huang R, Guo F, Liang Y, Xiang J, Lei S, et al. Selective Histone Deacetylase 6 Inhibitor 23BB Alleviated Rhabdomyolysis-Induced Acute Kidney Injury by Regulating Endoplasmic Reticulum Stress and Apoptosis. Front Pharmacol. 2018;9:274. doi: 10.3389/fphar.2018.00274 29632491

17. Shi Y, Xu L, Tang J, Fang L, Ma S, Ma X, et al. Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury. Am J Physiol Renal Physiol. 2017;312(3):F502–F15. doi: 10.1152/ajprenal.00546.2016 28052874

18. Tang J, Shi Y, Liu N, Xu L, Zang X, Li P, et al. Blockade of histone deacetylase 6 protects against cisplatin-induced acute kidney injury. Clin Sci (Lond). 2018;132(3):339–59. doi: 10.1042/cs20171417 29358506

19. Cebotaru L, Liu Q, Yanda MK, Boinot C, Outeda P, Huso DL, et al. Inhibition of histone deacetylase 6 activity reduces cyst growth in polycystic kidney disease. Kidney Int. 2016;90(1):90–9. doi: 10.1016/j.kint.2016.01.026 27165822

20. Choi SY, Ryu Y, Kee HJ, Cho SN, Kim GR, Cho JY, et al. Tubastatin A suppresses renal fibrosis via regulation of epigenetic histone modification and Smad3-dependent fibrotic genes. Vascul Pharmacol. 2015;72:130–40. doi: 10.1016/j.vph.2015.04.006 25921924

21. Yang Z, Wang T, Wang F, Niu T, Liu Z, Chen X, et al. Discovery of Selective Histone Deacetylase 6 Inhibitors Using the Quinazoline as the Cap for the Treatment of Cancer. J Med Chem. 2016;59(4):1455–70. doi: 10.1021/acs.jmedchem.5b01342 26443078

22. Kim JH, Lee SS, Jung MH, Yeo HD, Kim HJ, Yang JI, et al. N-acetylcysteine attenuates glycerol-induced acute kidney injury by regulating MAPKs and Bcl-2 family proteins. Nephrol Dial Transplant. 2010;25(5):1435–43. doi: 10.1093/ndt/gfp659 20037173

23. Wang XX, Wan RZ, Liu ZP. Recent advances in the discovery of potent and selective HDAC6 inhibitors. Eur J Med Chem. 2018;143:1406–18. doi: 10.1016/j.ejmech.2017.10.040 29133060

24. Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, et al. HDAC6 is a microtubule-associated deacetylase. Nature. 2002;417(6887):455–8. doi: 10.1038/417455a 12024216

25. Verdel A, Curtet S, Brocard MP, Rousseaux S, Lemercier C, Yoshida M, et al. Active maintenance of mHDA2/mHDAC6 histone-deacetylase in the cytoplasm. Curr Biol. 2000;10(12):747–9. doi: 10.1016/s0960-9822(00)00542-x 10873806

26. Bolignano D, Donato V, Coppolino G, Campo S, Buemi A, Lacquaniti A, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a marker of kidney damage. Am J Kidney Dis. 2008;52(3):595–605. doi: 10.1053/j.ajkd.2008.01.020 18725016

27. Rabb H, Griffin MD, McKay DB, Swaminathan S, Pickkers P, Rosner MH, et al. Inflammation in AKI: Current Understanding, Key Questions, and Knowledge Gaps. Journal of the American Society of Nephrology. 2016;27(2):371–9. doi: 10.1681/ASN.2015030261 26561643

28. de Jesus Soares T, Costa RS, Balbi AP, Coimbra TM. Inhibition of nuclear factor-kappa B activation reduces glycerol-induced renal injury. J Nephrol. 2006;19(4):439–48. 17048201

29. Tang J, Shi Y, Liu N, Xu L, Zang X, Li P, et al. Blockade of histone deacetylase 6 protects against cisplatin-induced acute kidney injury. Clinical Science. 2018;132(3):339–59. doi: 10.1042/CS20171417 29358506

30. Sharawy MH, Abdelrahman RS, El-Kashef DH. Agmatine attenuates rhabdomyolysis-induced acute kidney injury in rats in a dose dependent manner. Life Sciences. 2018;208:79–86. doi: 10.1016/j.lfs.2018.07.019 30009822

31. Niu X, Yao Q, Li W, Zang L, Li W, Zhao J, et al. Harmine mitigates LPS-induced acute kidney injury through inhibition of the TLR4-NF-kappaB/NLRP3 inflammasome signalling pathway in mice. Eur J Pharmacol. 2019;849:160–9. doi: 10.1016/j.ejphar.2019.01.062 30716318

32. Meldrum KK, Hile K, Meldrum DR, Crone JA, Gearhart JP, Burnett AL. Simulated ischemia induces renal tubular cell apoptosis through a nuclear factor-kappaB dependent mechanism. J Urol. 2002;168(1):248–52. 12050551

33. Baldwin AS Jr. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 1996;14:649–83. doi: 10.1146/annurev.immunol.14.1.649 8717528

34. Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998;16:225–60. doi: 10.1146/annurev.immunol.16.1.225 9597130

35. Grilli M, Chiu JJ, Lenardo MJ. NF-kappa B and Rel: participants in a multiform transcriptional regulatory system. Int Rev Cytol. 1993;143:1–62. doi: 10.1016/s0074-7696(08)61873-2 8449662

36. Williams KA, Zhang M, Xiang S, Hu C, Wu JY, Zhang S, et al. Extracellular signal-regulated kinase (ERK) phosphorylates histone deacetylase 6 (HDAC6) at serine 1035 to stimulate cell migration. J Biol Chem. 2013;288(46):33156–70. doi: 10.1074/jbc.M113.472506 24089523

37. Kästle M, Woschee E, Grune T. Histone deacetylase 6 (HDAC6) plays a crucial role in p38MAPK-dependent induction of heme oxygenase-1 (HO-1) in response to proteasome inhibition. Free Radical Biology and Medicine. 2012;53(11):2092–101. doi: 10.1016/j.freeradbiomed.2012.09.023 23010497

38. Jung KH, Noh JH, Kim JK, Eun JW, Bae HJ, Chang YG, et al. Histone deacetylase 6 functions as a tumor suppressor by activating c-Jun NH2-terminal kinase-mediated beclin 1-dependent autophagic cell death in liver cancer. Hepatology. 2012;56(2):644–57. doi: 10.1002/hep.25699 22392728

39. Zhang D, Li J, Costa M, Gao J, Huang C. JNK1 mediates degradation HIF-1alpha by a VHL-independent mechanism that involves the chaperones Hsp90/Hsp70. Cancer Res. 2010;70(2):813–23. doi: 10.1158/0008-5472.CAN-09-0448 20068160

Článek vyšel v časopise


2019 Číslo 10
Nejčtenější tento týden