Kidney injury caused by intermittent hypoxia and intervention effect of edaravone in rats_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

LI Lifang ¹ , YUAN Xinhui ¹ , LIN Jizu ¹ , DUAN Yanni ¹ ,  YU Qin ²

1. The First Clinical Medical School of Lanzhou University, Lanzhou, Gansu 730000, P. R. China;
2. Department of Respiratory Medicine, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P. R. China;

Corresponding author：

YU Qin, Email: yuq701@163.com

Keywords：

Intermittent hypoxia; Oxidative stress; Kidney injury molecule 1; Edaravone; Kidney injury; Cell apoptosis

DOI：

10.7507/1671-6205.201808036

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Objective To investigate the mechanism of the early kidney injury in rats caused by intermittent hypoxia, and investigate the intervention effect of edaravone.Methods Eighty male Wistar rats were randomly divided into a control group (NC), an intermittent hypoxia group (IH), an intermittent hypoxia edaravone treatment group (IH+NE), and an intermittent hypoxia normal saline matched group (IH+NS). After 4 weeks of model establishment, serum urea nitrogen and creatinine concentration were determined. Pathological changes of kidney were observed under light microscope, and ultrastructural changes of glomeruli and renal tubules were observed under electron microscope. The kidney injury molecule 1 (KIM-1) protein was detected by immunohistochemistry. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), hydroxyl radical and Bcl-2 mRNA, Caspase-3 mRNA, Bax mRNA in homogenate of kidney tissue were measured.Results Serum urea nitrogen in each group showed no significant difference. Serum creatinine increased significantly in IH group and significantly decreased after edaravone treatment. There were no significant pathological damages in NC group under light and electron microscopy. IH group showed varying degrees of renal tubule damages compared with NC group. Compared with NC group, the mean optical density of KIM-1 protein in IH group and IH + NS group significantly increased (P<0.01), and the mean optical density of KIM-1 protein in IH+NE group significantly decreased (P<0.01). Compared with NC group, the activity of SOD in IH group and IH+NS group significantly decreased, the content of MDA and hydroxyl radical increased, the expression of Bcl-2 mRNA decreased, the expression of Caspase-3 mRNA and Bax mRNA increased, Bcl-2/Bax decreased. After edaravone intervention, the activity of SOD in kidney tissue of rats significantly increased, the content of MDA and hydroxyl radical significantly decreased, the expression of Bcl-2 mRNA increased, the expression of Caspase-3 mRNA and Bax mRNA decreased, Bcl-2/Bax increased.Conclusions Intermittent hypoxia can cause kidney injury through oxidative stress and regulation of Bcl-2, Bax and Caspase-3. KIM-1 may be used as a sensitive indicator for monitoring early kidney injury. Edaravone can prevent kidney injury induced by intermittent hypoxia though scavenging oxygen free radical, improving antioxidant capacity, regulating cell apoptosis mediated by regulating Bcl-2/Bax and Caspase-3.

Citation： LI Lifang, YUAN Xinhui, LIN Jizu, DUAN Yanni, YU Qin. Kidney injury caused by intermittent hypoxia and intervention effect of edaravone in rats. Chinese Journal of Respiratory and Critical Care Medicine, 2019, 18(4): 331-338. doi: 10.7507/1671-6205.201808036 Copy

1.	Heinzer R, Vat S, Marques-Vidal P, et al. Prevalence of sleep-disordered breathing in the general population: the HypnoLaus study. Lancet Respir Med, 2015, 3(4): 310-318.
2.	李娟芝, 余勤, 汪小亚, 等. 慢性间歇性低氧激活内质网应激介导大鼠肾脏损伤. 中国呼吸与危重监护杂志, 2017, 16(4): 450-453.
3.	Ichimura T, Bonventre JV, Bailly V, et al. Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem, 1998, 273(7): 4135-4142.
4.	Han WK, Bailly V, Abichandani R, et al. Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int, 2002, 62(1): 237-244.
5.	Bonventre JV, Yang L. Kidney injury molecule-1. Curr Opin Crit Care, 2010, 16(6): 556-561.
6.	Abassi Z, Shalabi A, Sohotnik R, et al. Urinary NGAL and KIM-1: biomarkers for assessment of acute ischemic kidney injury following nephron sparing surgery. J Urol, 2013, 189(4): 1559-1566.
7.	Ichimura T, Hung CC, Yang SA, et al. Kidney injury molecule-1: a tissue and urinary biomarker for nephrotoxicant-induced renal injury. Am J Physiol Renal Physiol, 2004, 286(3): F552-F563.
8.	Tu Y, Wang H, Sun R, et al. Urinary netrin-1 and KIM-1 as early biomarkers for septic acute kidney injury. Ren Fail, 2014, 36(10): 1559-1563.
9.	Banno M, Mizuno T, Kato H, et al. The radical scavenger edaravone prevents oxidative neurotoxicity induced by peroxynitrite and activated microglia. Neuropharmacology, 2005, 48(2): 283-290.
10.	Li C, Lu J, Zhang B. Development of a novel chronic intermittent hypoxia chamber. Sleep Breath, 2012, 16(1): 177-179.
11.	Wang X, Yu Q, Yue H, et al. Effect of intermittent hypoxia and rimonabant on glucose metabolism in rats: involvement of expression of GLUT4 in skeletal muscle. Med Sci Monit, 2015, 21: 3252-3260.
12.	李秀翠, 蔡晓红, 温正旺, 等. 间歇性低氧动物模型的建立及验证. 医学研究杂志, 2012, 41(7): 57-61.
13.	Carpagnano GE, Kharitonov SA, Resta O, et al. Increased 8-isoprostane and interleukin-6 in breath condensate of obstructive sleep apnea patients. Chest, 2002, 122(4): 1162-1167.
14.	Doi K, Suzuki Y, Nakao A, et al. Radical scavenger edaravone developed for clinical use ameliorates ischemia/reperfusion injury in rat kidney. Kidney Int, 2004, 65(5): 1714-1723.
15.	余勤, 汪小亚, 岳红梅, 等. 血清胱蛋白酶抑制剂 C 及尿酶对阻塞性睡眠呼吸暂停低通气综合征早期肾功能损害的诊断价值. 兰州大学学报, 2008, 34(1): 15-16.
16.	李莉, 余勤. 阻塞性睡眠呼吸暂停低通气综合征患者血清胱蛋白酶抑制剂 C 水平及尿系列酶活性的变化. 中国呼吸与危重监护杂志, 2006, 5(5): 366-369.
17.	Fontanilla J, Han WK. Kidney injury molecule-1 as an early detection tool for acute kidney injury and other kidney diseases. Expert Opin Med Diagn, 2011, 5(2): 161-173.
18.	Vaidya VS, Ozer JS, Dieterle F, et al. Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies. Nat Biotechnol, 2010, 28(5): 478-485.
19.	寇育乐, 张盼盼, 王红阳, 等. 血管紧张素Ⅱ与氧化应激对慢性间歇低氧大鼠肺组织损伤的影响. 中华结核和呼吸杂志, 2015, 38(8): 612-616.
20.	Rajesh KG, Sasaguri S, Zhitian Z, et al. Second window of ischemic preconditioning regulates mitochondrial permeability transition pore by enhancing Bcl-2 expression. Cardiovasc Res, 2003, 59(2): 297-307.
21.	Renault TT, Teijido O, Antonsson B, et al. Regulation of Bax mitochondrial localization by Bcl-2 and Bcl-xL: keep your friends close but your enemies closer. Int J Biochem Cell Biol, 2013, 45(1): 64-67.
22.	Yang T, Zhang YL, Li YL, et al. High amounts of fluoride induce apoptosis/cell death in matured ameloblast-like LS8 cells by downregulating Bcl-2. Arch Oral Biol, 2013, 58(9): 1165-1173.
23.	Vander Heiden MG, Li XX, Gottleib E, et al. Bcl-xL promotes the open configuration of the voltage-dependent anion channel and metabolite passage through the outer mitochondrial membrane. J Biol Chem, 2001, 276(22): 19414-19419.
24.	Tan C, Dlugosz PJ, Peng J, et al. Auto-activation of the apoptosis protein Bax increases mitochondrial membrane permeability and is inhibited by Bcl-2. J Biol Chem, 2006, 281(21): 14764-14775.
25.	Renault TT, Manon S. Bax: addressed to kill. Biochimie, 2011, 93(9): 1379-1391.
26.	Taeger CD, Muller-Seubert W, Horch RE, et al. Ischaemia-related cell damage in extracorporeal preserved tissue - new findings with a novel perfusion model. J Cell Mol Med, 2014, 18(5): 885-894.
27.	Snigdha S, Smith ED, Prieto GA, et al. Caspase-3 activation as a bifurcation point between plasticity and cell death. Neurosci Bull, 2012, 28(1): 14-24.

1. Heinzer R, Vat S, Marques-Vidal P, et al. Prevalence of sleep-disordered breathing in the general population: the HypnoLaus study. Lancet Respir Med, 2015, 3(4): 310-318.
2. 李娟芝, 余勤, 汪小亚, 等. 慢性间歇性低氧激活内质网应激介导大鼠肾脏损伤. 中国呼吸与危重监护杂志, 2017, 16(4): 450-453.
3. Ichimura T, Bonventre JV, Bailly V, et al. Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem, 1998, 273(7): 4135-4142.
4. Han WK, Bailly V, Abichandani R, et al. Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int, 2002, 62(1): 237-244.
5. Bonventre JV, Yang L. Kidney injury molecule-1. Curr Opin Crit Care, 2010, 16(6): 556-561.
6. Abassi Z, Shalabi A, Sohotnik R, et al. Urinary NGAL and KIM-1: biomarkers for assessment of acute ischemic kidney injury following nephron sparing surgery. J Urol, 2013, 189(4): 1559-1566.
7. Ichimura T, Hung CC, Yang SA, et al. Kidney injury molecule-1: a tissue and urinary biomarker for nephrotoxicant-induced renal injury. Am J Physiol Renal Physiol, 2004, 286(3): F552-F563.
8. Tu Y, Wang H, Sun R, et al. Urinary netrin-1 and KIM-1 as early biomarkers for septic acute kidney injury. Ren Fail, 2014, 36(10): 1559-1563.
9. Banno M, Mizuno T, Kato H, et al. The radical scavenger edaravone prevents oxidative neurotoxicity induced by peroxynitrite and activated microglia. Neuropharmacology, 2005, 48(2): 283-290.
10. Li C, Lu J, Zhang B. Development of a novel chronic intermittent hypoxia chamber. Sleep Breath, 2012, 16(1): 177-179.
11. Wang X, Yu Q, Yue H, et al. Effect of intermittent hypoxia and rimonabant on glucose metabolism in rats: involvement of expression of GLUT4 in skeletal muscle. Med Sci Monit, 2015, 21: 3252-3260.
12. 李秀翠, 蔡晓红, 温正旺, 等. 间歇性低氧动物模型的建立及验证. 医学研究杂志, 2012, 41(7): 57-61.
13. Carpagnano GE, Kharitonov SA, Resta O, et al. Increased 8-isoprostane and interleukin-6 in breath condensate of obstructive sleep apnea patients. Chest, 2002, 122(4): 1162-1167.
14. Doi K, Suzuki Y, Nakao A, et al. Radical scavenger edaravone developed for clinical use ameliorates ischemia/reperfusion injury in rat kidney. Kidney Int, 2004, 65(5): 1714-1723.
15. 余勤, 汪小亚, 岳红梅, 等. 血清胱蛋白酶抑制剂 C 及尿酶对阻塞性睡眠呼吸暂停低通气综合征早期肾功能损害的诊断价值. 兰州大学学报, 2008, 34(1): 15-16.
16. 李莉, 余勤. 阻塞性睡眠呼吸暂停低通气综合征患者血清胱蛋白酶抑制剂 C 水平及尿系列酶活性的变化. 中国呼吸与危重监护杂志, 2006, 5(5): 366-369.
17. Fontanilla J, Han WK. Kidney injury molecule-1 as an early detection tool for acute kidney injury and other kidney diseases. Expert Opin Med Diagn, 2011, 5(2): 161-173.
18. Vaidya VS, Ozer JS, Dieterle F, et al. Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies. Nat Biotechnol, 2010, 28(5): 478-485.
19. 寇育乐, 张盼盼, 王红阳, 等. 血管紧张素Ⅱ与氧化应激对慢性间歇低氧大鼠肺组织损伤的影响. 中华结核和呼吸杂志, 2015, 38(8): 612-616.
20. Rajesh KG, Sasaguri S, Zhitian Z, et al. Second window of ischemic preconditioning regulates mitochondrial permeability transition pore by enhancing Bcl-2 expression. Cardiovasc Res, 2003, 59(2): 297-307.
21. Renault TT, Teijido O, Antonsson B, et al. Regulation of Bax mitochondrial localization by Bcl-2 and Bcl-xL: keep your friends close but your enemies closer. Int J Biochem Cell Biol, 2013, 45(1): 64-67.
22. Yang T, Zhang YL, Li YL, et al. High amounts of fluoride induce apoptosis/cell death in matured ameloblast-like LS8 cells by downregulating Bcl-2. Arch Oral Biol, 2013, 58(9): 1165-1173.
23. Vander Heiden MG, Li XX, Gottleib E, et al. Bcl-xL promotes the open configuration of the voltage-dependent anion channel and metabolite passage through the outer mitochondrial membrane. J Biol Chem, 2001, 276(22): 19414-19419.
24. Tan C, Dlugosz PJ, Peng J, et al. Auto-activation of the apoptosis protein Bax increases mitochondrial membrane permeability and is inhibited by Bcl-2. J Biol Chem, 2006, 281(21): 14764-14775.
25. Renault TT, Manon S. Bax: addressed to kill. Biochimie, 2011, 93(9): 1379-1391.
26. Taeger CD, Muller-Seubert W, Horch RE, et al. Ischaemia-related cell damage in extracorporeal preserved tissue - new findings with a novel perfusion model. J Cell Mol Med, 2014, 18(5): 885-894.
27. Snigdha S, Smith ED, Prieto GA, et al. Caspase-3 activation as a bifurcation point between plasticity and cell death. Neurosci Bull, 2012, 28(1): 14-24.

Chinese Journal of Respiratory and Critical Care Medicine

Kidney injury caused by intermittent hypoxia and intervention effect of edaravone in rats

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