Histone deacetylases 6 inhibitor 23BB alleviated myoglobin-induced endoplasmic reticulum stress in tubular epithelial cells_West China Medical Journal

Authors：

LIN Lin ¹ , GUO Fan ² ,  MA Liang ² , FENG Yuying ² , YANG Zhuang ³

1. West-district Outpatient Department, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
3. State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

MA Liang, Email: liang_m@scu.edu.cn

Keywords：

Rhabdomyolysis-induced acute kidney injury; Myoglobin; Histone deacetylases 6 inhibitor; Tubular epithelial cells; Endoplasmic reticulum stress

DOI：

10.7507/1002-0179.201806101

Video：

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Abstract Full text Figures/Tables Video References Cited by

ObjectiveTo investigate the protective effects and mechanism of selective histone deacetylases 6 (HDAC6) inhibitor 23BB in myoglobin-induced proximal tubular cell lines (HK-2).MethodsHK-2 cells were divided into 5 groups, including control group, myoglobin (200 μmol/L) group, myoglobin (200 μmol/L)+23BB (1.25 nmol/L) group, myoglobin (200 μmol/L)+4-phenylbutyric acid (2 mmol/L) group, and myoglobin (200 μmol/L)+23BB (1.25 nmol/L)+tunicamycin (25 ng/mL) group. Cells were collected at 24 hours after treatment. The endoplasmic reticulum (ER) stress-related gene mRNA level and marker protein expression were evaluated by RT-PCR and Western blotting, including glucose regulated protein 78 (GRP78), C/EBP homology protein (CHOP), inositol-requiring enzyme 1 (IRE1), PKR-like ER kinase (PERK), and activating transcription factor 6.ResultsIn in vitro study, ER stress-related mRNA of GRP78, IRE1α, PERK, and CHOP and marker protein expression of GRP78 and CHOP were found to increase in response to myoglobin treatment. Either administration of 23BB or 4-PBA could alleviate myoglobin-induced these changes.ConclusionThe protective effect of HDAC6 inhibitor 23BB is through the inhibition of myoglobin-induced ER stress in HK-2 cells.

Citation： LIN Lin, GUO Fan, MA Liang, FENG Yuying, YANG Zhuang. Histone deacetylases 6 inhibitor 23BB alleviated myoglobin-induced endoplasmic reticulum stress in tubular epithelial cells. West China Medical Journal, 2018, 33(7): 881-886. doi: 10.7507/1002-0179.201806101 Copy

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2.	Raymond V, Sukriu SM, Ekrem E, et al. Rhabdomyolysis. J Amer Soc Nephrol. 2000, 11(8): 1553-1561.
3.	Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA, 2004, 292(21): 2585-2590.
4.	Mcmahon GM, Zeng XX, Waikar SS. A risk prediction score for kidney failure or mortality in rhabdomyolysis. JAMA Intern Med, 2013, 173(19): 1821-1828.
5.	Petejova N, Martinek A. Acute kidney injury due to rhabdomyolysis and renal replacement therapy: a critical review. Crit Care, 2014, 18(3): 224.
6.	张雪梅, 唐怡, 杨莹莹, 等. 肌红蛋白诱导的内质网应激及细胞凋亡在挤压综合征中的机制初探. 四川大学学报: 医学版, 2014, 46(1): 22-26.
7.	Shi Y, Xu L, Tang J, et al. Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury. Am J Physiol Renal Physiol, 2017, 312(3): F502-F515.
8.	Tang JH, Yan YL, Zhao TC, et al. Class I HDAC activity is required for renal protection and regeneration after acute kidney injury. Am J Physiol Renal Physiol, 2014, 307(3): F303-F316.
9.	Yang Z, Wang TJ, Wang F, 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, SI): 1455-1470.
10.	Feng Y, Huang R, Guo F, 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.
11.	Huerta-Alardín AL, Varon J, Marik PE. Bench-to-bedside review: rhabdomyolysis--an overview for clinicians. Crit Care, 2005, 9(2): 158-169.
12.	Holt S, Moore K. Pathogenesis of renal failure in rhabdomyolysis: the role of myoglobin. Exp Nephrol, 2000, 8(2): 72-76.
13.	Boutaud O, Roberts LJ 2nd. Mechanism-based therapeutic approaches to rhabdomyolysis-induced renal failure. Free Radic Biol Med, 2011, 51(5, SI): 1062-1067.
14.	Panizo N, Rubio-Navarro A, Manuel Amaro-Villalobos J, et al. Molecular mechanisms and novel therapeutic approaches to rhabdo-myolysis-induced acute kidney injury. Kidney Blood Press Res, 2015, 40(5): 520-532.
15.	Zhou J, Kong D, Zhang X, et al. Myoglobin-induced apoptosis: two pathways related to endoplasmic reticulum stress. Ther Apher Dial, 2012, 16(3): 272-280.
16.	Hubbert C, Guardiola A, Shao R, et al. HDAC6 is a microtubule-associated deacetylase. Nature, 2002, 417(6887): 455-458.

1. Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. New Eng J Med, 2009, 361(1): 62-72.
2. Raymond V, Sukriu SM, Ekrem E, et al. Rhabdomyolysis. J Amer Soc Nephrol. 2000, 11(8): 1553-1561.
3. Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA, 2004, 292(21): 2585-2590.
4. Mcmahon GM, Zeng XX, Waikar SS. A risk prediction score for kidney failure or mortality in rhabdomyolysis. JAMA Intern Med, 2013, 173(19): 1821-1828.
5. Petejova N, Martinek A. Acute kidney injury due to rhabdomyolysis and renal replacement therapy: a critical review. Crit Care, 2014, 18(3): 224.
6. 张雪梅, 唐怡, 杨莹莹, 等. 肌红蛋白诱导的内质网应激及细胞凋亡在挤压综合征中的机制初探. 四川大学学报: 医学版, 2014, 46(1): 22-26.
7. Shi Y, Xu L, Tang J, et al. Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury. Am J Physiol Renal Physiol, 2017, 312(3): F502-F515.
8. Tang JH, Yan YL, Zhao TC, et al. Class I HDAC activity is required for renal protection and regeneration after acute kidney injury. Am J Physiol Renal Physiol, 2014, 307(3): F303-F316.
9. Yang Z, Wang TJ, Wang F, 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, SI): 1455-1470.
10. Feng Y, Huang R, Guo F, 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.
11. Huerta-Alardín AL, Varon J, Marik PE. Bench-to-bedside review: rhabdomyolysis--an overview for clinicians. Crit Care, 2005, 9(2): 158-169.
12. Holt S, Moore K. Pathogenesis of renal failure in rhabdomyolysis: the role of myoglobin. Exp Nephrol, 2000, 8(2): 72-76.
13. Boutaud O, Roberts LJ 2nd. Mechanism-based therapeutic approaches to rhabdomyolysis-induced renal failure. Free Radic Biol Med, 2011, 51(5, SI): 1062-1067.
14. Panizo N, Rubio-Navarro A, Manuel Amaro-Villalobos J, et al. Molecular mechanisms and novel therapeutic approaches to rhabdo-myolysis-induced acute kidney injury. Kidney Blood Press Res, 2015, 40(5): 520-532.
15. Zhou J, Kong D, Zhang X, et al. Myoglobin-induced apoptosis: two pathways related to endoplasmic reticulum stress. Ther Apher Dial, 2012, 16(3): 272-280.
16. Hubbert C, Guardiola A, Shao R, et al. HDAC6 is a microtubule-associated deacetylase. Nature, 2002, 417(6887): 455-458.

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