The mechanism of renal injury induced by endoplasmic reticulum stress in rats with intermittent hypoxia and the intervention effect of losartan_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

WANG Wei ¹ ^△ , ZHANG Rongli ¹ , LING Jizu ² ,  YU Qin ³

1. First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, P. R. China;
2. Department of Pediatrics, First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P. R. China;
3. Department of Respiratory and Critical Care Medicine, First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P. R. China;

Corresponding author：

YU Qin, Email: yuq701@163.com

Keywords：

Obstructive sleep apnea hypopnea syndrome; Intermittent hypoxia; Losartan; Endoplasmic reticulum stress; Apoptosis

DOI：

10.7507/1671-6205.201901009

Video：

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Objective To explore the mechanism of renal tubular epithelial cell apoptosis induced by endoplasmic reticulum stress in rats with intermittent hypoxia (IH) and the intervention effect of losartan.Methods Sixty SPF grade healthy male SD rats were randomly divided into four groups (15 rats in each group), namely as group A (control group), group B (IH group), group C (IH+losartan group), and group D (IH+saline group). The group C and D were intraperitoneally injected with losartan 30 mg/kg and the same dose of saline 30 minutes daily before the experiment, and then the group B, C and D were placed in the intermittent hypoxia chamber. After 6 weeks of modeling, serum of the rats was sampled to detect the renal function. Hematoxylin-eosin staining was used to observe histomorphological changes of the kidney; transmission electron microscopy was used to observe ultrastructural changes of the kidney; TUNEL was used to detect apoptotic index of the renal tubular epithelial cells; and RT-PCR method was used to detect expressions of caspase-12, JNK and CHOP mRNA in the kidney.Results The differences of renal function among these four groups were statistically significant (all P<0.05). Hematoxylin-eosin staining and transmission electron microscopy showed the histomorphological and ultrastructural changes of the kidneys in group B, C and D compared with group A, and the damages in group B and D were more significant. TUNEL results showed that the apoptotic index of renal tubular epithelial cells in group B and D was significantly higher than that in group A (P<0.01), while that in group C was significantly lower than that in group B and D (all P<0.01). RT-PCR results showed that caspase-12, JNK and CHOP mRNA expressions were significantly higher in group B and D than those in group A (all P<0.01); caspase-12 mRNA expression was significantly lower in group C than that in group B and D (P<0.01; P<0.05); and CHOP mRNA expression was significantly lower in group C than that in group B and D (all P<0.01).Conclusions IH may induce apoptosis of renal tubular epithelial cells by activating endoplasmic reticulum stress through caspase-12, JNK and CHOP. Losartan has protective effects on the kidney of rats with intermittent hypoxia. Its mechanism may be related to the inhibition of apoptotic pathways mediated by endoplasmic reticulum stress.

Citation： WANG Wei, ZHANG Rongli, LING Jizu, YU Qin. The mechanism of renal injury induced by endoplasmic reticulum stress in rats with intermittent hypoxia and the intervention effect of losartan. Chinese Journal of Respiratory and Critical Care Medicine, 2020, 19(6): 592-597. doi: 10.7507/1671-6205.201901009 Copy

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2.	Young T, Skatrud J, Peppard PE. Risk factors for obstructive sleep apnea in adults. JAMA, 2004, 291(16): 2013-2016.
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12.	Jin ZN, Wei YX. Meta-analysis of effects of obstructive sleep apnea on the renin-angiotensin-aldosterone system. J Geriatr Cardiol, 2016, 13(4): 333-343.
13.	Torres G, Sánchez-de-la-Torre M, Barbé F. Relationship between OSA and hypertension. Chest, 2015, 148(3): 824-832.
14.	Yamauchi M, Nakano H, Maekawa J, et al. Oxidative stress in obstructive sleep apnea. Chest, 2005, 127(5): 1674-1679.
15.	Chen HL, Lu CH, Lin HC, et al. White matter damage and systemic inflammation in obstructive sleep apnea. Sleep, 2015, 38(3): 361-370.
16.	Kohler M, Stradling JR. Mechanisms of vascular damage in obstructive sleep apnea. Nat Rev Cardiol, 2010, 7(12): 677-685.
17.	张秀娟, 李庆云, 许华俊. 睡眠呼吸暂停模式间歇低氧动物模型的建立及应用. 中华结核和呼吸杂志, 2011, 34(10): 777-779.
18.	Wang M, Kaufman RJ. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature, 2016, 529(7586): 326-335.
19.	Yang Y, Sun M, Shan Y, et al. Endoplasmic reticulum stress-mediated apoptotic pathway is involved in corpus luteum regression in rats. Reprod Sci, 2015, 22(5): 572-584.
20.	Zalucky AA, Nicholl DD, Hanly PJ, et al. Nocturnal hypoxemia severity and renin-angiotensin system activity in obstructive sleep apnea. Am J Respir Crit Care Med, 2015, 192(7): 873-880.
21.	Duan Q, Song P, Ding Y, et al. Activation of AMP-activated protein kinase by metformin ablates angiotensin Ⅱ-induced endoplasmic reticulum stress and hypertension in mice in vivo. Br J Pharmacol, 2017, 174(13): 2140-2151.
22.	Iurlaro R, Muñoz-Pinedo C. Cell death induced by endoplasmic reticulum stress. FEBS J, 2016, 283(14): 2640-2652.

1. Jordan AS, McSharry DG, Malhotra A. Adult obstructive sleep apnoea. Lancet, 2014, 383(9918): 736-747.
2. Young T, Skatrud J, Peppard PE. Risk factors for obstructive sleep apnea in adults. JAMA, 2004, 291(16): 2013-2016.
3. 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): 350-353.
4. 高佳, 朱选风, 张希龙, 等. 脂联素抑制内质网应激干预慢性间歇性缺氧所致肾损伤. 中华老年多器官疾病杂志, 2017, 16(9): 687-692.
5. 冯丹, 姚尚龙, 尚游, 等. 血管紧张素Ⅱ受体阻断剂对大鼠机械通气所致肺损伤的保护作用. 中华急诊医学杂志, 2007, 16(9): 940-944.
6. Li C, Lu J, Zhang B. Development of a novel chronic intermittent hypoxia chamber. Sleep Breath, 2012, 16(1): 177-179.
7. 张秀丽, 余勤, 汪小亚, 等. CD73 在慢性间歇性低氧合并高脂饮食条件下大鼠心脏损伤中的作用. 中国呼吸与危重监护杂志, 2017, 16(5): 478-483.
8. Ahmed SB, Ronksley PE, Hemmelgarn BR, et al. Nocturnal hypoxia and loss of kidney function. PLoS One, 2011, 6(4): e19029.
9. Dewan NA, Nieto FJ, Somers VK. Intermittent hypoxemia and OSA: implications for comorbidities. Chest, 2015, 147(1): 266-274.
10. Yaggi HK, Strohl KP. Adult obstructive sleep apnea/hypopnea syndrome: definitions, risk factors, and pathogenesis. Clin Chest Med, 2010, 31(2): 179-186.
11. Beecroft JM, Hoffstein V, Pierratos A, et al. Nocturnal haemodialysis increases pharyngeal size in patients with sleep apnoea and end-stage renal disease. Nephrol Dial Transplant, 2008, 23(2): 673-679.
12. Jin ZN, Wei YX. Meta-analysis of effects of obstructive sleep apnea on the renin-angiotensin-aldosterone system. J Geriatr Cardiol, 2016, 13(4): 333-343.
13. Torres G, Sánchez-de-la-Torre M, Barbé F. Relationship between OSA and hypertension. Chest, 2015, 148(3): 824-832.
14. Yamauchi M, Nakano H, Maekawa J, et al. Oxidative stress in obstructive sleep apnea. Chest, 2005, 127(5): 1674-1679.
15. Chen HL, Lu CH, Lin HC, et al. White matter damage and systemic inflammation in obstructive sleep apnea. Sleep, 2015, 38(3): 361-370.
16. Kohler M, Stradling JR. Mechanisms of vascular damage in obstructive sleep apnea. Nat Rev Cardiol, 2010, 7(12): 677-685.
17. 张秀娟, 李庆云, 许华俊. 睡眠呼吸暂停模式间歇低氧动物模型的建立及应用. 中华结核和呼吸杂志, 2011, 34(10): 777-779.
18. Wang M, Kaufman RJ. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature, 2016, 529(7586): 326-335.
19. Yang Y, Sun M, Shan Y, et al. Endoplasmic reticulum stress-mediated apoptotic pathway is involved in corpus luteum regression in rats. Reprod Sci, 2015, 22(5): 572-584.
20. Zalucky AA, Nicholl DD, Hanly PJ, et al. Nocturnal hypoxemia severity and renin-angiotensin system activity in obstructive sleep apnea. Am J Respir Crit Care Med, 2015, 192(7): 873-880.
21. Duan Q, Song P, Ding Y, et al. Activation of AMP-activated protein kinase by metformin ablates angiotensin Ⅱ-induced endoplasmic reticulum stress and hypertension in mice in vivo. Br J Pharmacol, 2017, 174(13): 2140-2151.
22. Iurlaro R, Muñoz-Pinedo C. Cell death induced by endoplasmic reticulum stress. FEBS J, 2016, 283(14): 2640-2652.

Chinese Journal of Respiratory and Critical Care Medicine

The mechanism of renal injury induced by endoplasmic reticulum stress in rats with intermittent hypoxia and the intervention effect of losartan

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