Chronic intermittent hypoxia induces renal injury in rats by activating endoplasmic reticulum stress_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

LI Juanzhi ¹ ,  YU Qin ² , WANG Xiaoya ² , ZHANG Xiuli ¹ , ZHAO Hong ¹

1. First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, P.R.China;
2. Department of Respiratory 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; Chronic intermittent hypoxia; High fat diet; Endoplasmic reticulum stress; Renal injury

DOI：

10.7507/1671-6205.201702002

Video：

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Objective To explore the mechanism of chronic intermittent hypoxia (CIH) on renal damage with normal diet and high-fat diet. Methods Twenty-four healthy male Wistar rats of SPF grade were randomly divided into 4 groups (n=6 in each group), namely group A (normoxia and common diet), group B (normoxia and high fat diet), Group C (CIH and common diet), and group D (CIH and high fat diet). The serum cystatin C (Cys-C) was measured and the renal CHOP protein was detected by immunohistochemistry. The ultrastructural changes of glomeruli and renal tubules were observed under electron microscope. Results The levels of Cys-C in group B, group C and group D were significantly higher than those in group A (P<0.05). The mean density of endoplasmic reticulum stress (ERS) marker protein CHOP in group B, group C and group D was significantly higher than that in group A (P<0.05). Electron microscope revealed focal nuclear pyknosis in the partly renal tubular epithelial cells, sparse and scattered brush border in group B and group C, also revealed nuclear pyknosis in a large number of tubular epithelial cells, sparse and scattered brush border in group D. Conclusion CIH can activate the ERS mediated renal tubular epithelial apoptosis, thus induce ultrastructure changes and damage of kidney.

Citation： LI Juanzhi, YU Qin, WANG Xiaoya, ZHANG Xiuli, ZHAO Hong. Chronic intermittent hypoxia induces renal injury in rats by activating endoplasmic reticulum stress. Chinese Journal of Respiratory and Critical Care Medicine, 2017, 16(4): 350-353. doi: 10.7507/1671-6205.201702002 Copy

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2.	Uyar M, Davutoglu V. Obstructive sleep apnoea: a stand-alone risk factor for chronic kidney disease. Nephrol Dial Transplant, 2011, 26(8): 2718; author reply 2718-2719.
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5.	Chen S, He FF, Wang H, et al. Calcium entry via TRPC6 mediates albumin overload-induced endoplasmic reticulum stress and apoptosis in podocytes. Cell Calcium, 2011, 50(6): 523-529.
6.	Lim JC, Lim SK, Park MJ, et al. Cannabinoid receptor 1 mediates high glucose-induced apoptosis via endoplasmic reticulum stress in primary cultured rat mesangial cells. Am J Physiol Renal Physiol, 2011, 301(1): F179-188.
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8.	Wiart C. Comment on " The endoplasmic reticulum stress response is involved in apoptosis induced by aloe-emodin in HK-2 cells by Zhu et al. (2012). Food Chem Toxicol, 2013, 51: 458.
9.	Maclean KN, Greiner LS, Evans JR, et al. Cystathionine protects against endoplasmic reticulum stress-induced lipid accumulation, tissue injury, and apoptotic cell death. J Biol Chem, 2012, 287(38): 31994-32005.
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12.	劉蔚, 唐繼海, 李崢嶸, 等 Cys-c、hs-CRP 和尿微量白蛋白在糖尿病患者腎功能早期損傷中的診斷價值. 中國實驗診斷學, 2012, 16(12): 2260-2262.
13.	余勤, 汪小亞, 岳紅梅, 等. 血清胱蛋白酶抑制劑 C 及尿酶對阻塞性睡眠呼吸暫停低通氣綜合征早期腎功能損害的診斷價值. 蘭州大學學報(醫學版), 2008, 34(1): 13-16.
14.	夏秋萍, 陳建榮, 蔡映云, 等. OSAHS 患者血清 8-isoPG、LTB4、TNF-α、IL-10 和 Hs-CRP 檢測的臨床意義. 中國呼吸與危重監護雜志, 2009, 8(3): 262-266.
15.	寇育樂, 張盼盼, 王紅陽, 等. 血管緊張素Ⅱ與氧化應激對慢性間歇低氧大鼠肺組織損傷的影響. 中華結核和呼吸雜志, 2015, 38(0): 612-616.
16.	李慶云. 慢性間歇低氧與氧化應激. 中華結核和呼吸雜志, 2008, 31(9): 646-647.
17.	Munoz-Garcia B, Moreno JA, Lopez-Franco O, et al. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) enhances vascular and renal damage induced by hyperlipidemic diet in ApoE-knockout mice. Arterioscler Thromb Vasc Biol, 2009, 29(12): 2061-2068.
18.	Zhang R, Yu Y, Deng J, et al. Sesamin ameliorates high-fat diet-induced dyslipidemia and kidney injury by reducing oxidative stress. Nutrients, 2016, 8(5):.
19.	Osipov RM, Bianchi C, Feng J, et al. Effect of hypercholesterolemia on myocardial necrosis and apoptosis in the setting of ischemia-reperfusion. Circulation, 2009, 120(11 Suppl): S22-30.
20.	Minville-Walz M, Gresti J, Pichon L, et al. Distinct regulation of stearoyl-CoA desaturase 1 gene expression by cis and trans C18: 1 fatty acids in human aortic smooth muscle cells. Genes Nutr, 2012, 7(2): 209-216.
21.	石志輝, 徐麟皓, 周銳. 牛磺熊去氧膽酸鈉抑制小鼠間歇性低氧模型肺組織中內質網應激的激活. 中南大學學報: 醫學版, 2015, 40(11): 1165-1172.
22.	Shin C, Kim JK, Kim JH, et al. Increased cell-free DNA concentrations in patients with obstructive sleep apnea. Psychiatry Clin Neurosci, 2008, 62(6): 721-727.
23.	郝敏, 賈雪梅, 汪淵, 等. 高脂飲食大鼠腎組織中細胞凋亡及 Bcl-2 和 Bax 的表達. 安徽醫科大學學報, 2009, (2): 191-194.
24.	邱艷麗, 李巧稚, 鄭亞琴, 等. 內質網應激與氧化應激: 惡性循環還是雙刃劍?. 實用藥物與臨床, 2016, 19(8): 1037-1041.
25.	Hetz C, Chevet E, Harding HP. Targeting the unfolded protein response in disease. Nat Rev Drug Discov, 2013, 12(9): 703-719.
26.	Wang S, Kaufman RJ. The impact of the unfolded protein response on human disease. J Cell Biol, 2012, 197(7): 857-867.
27.	Xu LH, Xie H, Shi ZH, et al. Critical role of endoplasmic reticulum stress in chronic intermittent hypoxia-induced deficits in synaptic plasticity and long-term memory. Antioxid Redox Signal, 2015, 23(9): 695-710.
28.	Cai XH, Li XC, Jin SW, et al. Endoplasmic reticulum stress plays critical role in brain damage after chronic intermittent hypoxia in growing rats. Exp Neurol, 2014, 257: 148-156.
29.	Sanchez AM, Martinez-Botas J, Malagarie-Cazenave S, et al. Induction of the endoplasmic reticulum stress protein GADD153/CHOP by capsaicin in prostate PC-3 cells: a microarray study. Biochem Biophys Res Commun, 2008, 372(4): 785-791.

1. Lindberg E, Gislason T. Epidemiology of sleep-related obstructive breathing. Sleep Med Rev, 2000, 4(5): 411-433.
2. Uyar M, Davutoglu V. Obstructive sleep apnoea: a stand-alone risk factor for chronic kidney disease. Nephrol Dial Transplant, 2011, 26(8): 2718; author reply 2718-2719.
3. Chhunchha B, Fatma N, Kubo E, et al. Curcumin abates hypoxia-induced oxidative stress based-ER stress-mediated cell death in mouse hippocampal cells (HT22) by controlling Prdx6 and NF-kappaB regulation. Am J Physiol Cell Physiol, 2013, 304(7): C636-655.
4. Chen X, Kintner DB, Luo J, et al. Endoplasmic reticulum Ca²⁺ dysregulation and endoplasmic reticulum stress following in vitro neuronal ischemia: role of Na⁺-K⁺-Cl^-cotransporter. J Neurochem, 2008, 106(4): 1563-1576.
5. Chen S, He FF, Wang H, et al. Calcium entry via TRPC6 mediates albumin overload-induced endoplasmic reticulum stress and apoptosis in podocytes. Cell Calcium, 2011, 50(6): 523-529.
6. Lim JC, Lim SK, Park MJ, et al. Cannabinoid receptor 1 mediates high glucose-induced apoptosis via endoplasmic reticulum stress in primary cultured rat mesangial cells. Am J Physiol Renal Physiol, 2011, 301(1): F179-188.
7. Chiang CK, Hsu SP, Wu CT, et al. Endoplasmic reticulum stress implicated in the development of renal fibrosis. Mol Med, 2011, 17(11-12): 1295-1305.
8. Wiart C. Comment on " The endoplasmic reticulum stress response is involved in apoptosis induced by aloe-emodin in HK-2 cells by Zhu et al. (2012). Food Chem Toxicol, 2013, 51: 458.
9. Maclean KN, Greiner LS, Evans JR, et al. Cystathionine protects against endoplasmic reticulum stress-induced lipid accumulation, tissue injury, and apoptotic cell death. J Biol Chem, 2012, 287(38): 31994-32005.
10. 丁巍. 內質網應激在腎小管上皮細胞凋亡中的作用及機制研究 [D];復旦大學, 2012.
11. Wang H, Tian JL, Feng SZ, et al. The organ specificity in pathological damage of chronic intermittent hypoxia: an experimental study on rat with high-fat diet. Sleep Breath, 2013, 17(3): 957-965.
12. 劉蔚, 唐繼海, 李崢嶸, 等 Cys-c、hs-CRP 和尿微量白蛋白在糖尿病患者腎功能早期損傷中的診斷價值. 中國實驗診斷學, 2012, 16(12): 2260-2262.
13. 余勤, 汪小亞, 岳紅梅, 等. 血清胱蛋白酶抑制劑 C 及尿酶對阻塞性睡眠呼吸暫停低通氣綜合征早期腎功能損害的診斷價值. 蘭州大學學報(醫學版), 2008, 34(1): 13-16.
14. 夏秋萍, 陳建榮, 蔡映云, 等. OSAHS 患者血清 8-isoPG、LTB4、TNF-α、IL-10 和 Hs-CRP 檢測的臨床意義. 中國呼吸與危重監護雜志, 2009, 8(3): 262-266.
15. 寇育樂, 張盼盼, 王紅陽, 等. 血管緊張素Ⅱ與氧化應激對慢性間歇低氧大鼠肺組織損傷的影響. 中華結核和呼吸雜志, 2015, 38(0): 612-616.
16. 李慶云. 慢性間歇低氧與氧化應激. 中華結核和呼吸雜志, 2008, 31(9): 646-647.
17. Munoz-Garcia B, Moreno JA, Lopez-Franco O, et al. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) enhances vascular and renal damage induced by hyperlipidemic diet in ApoE-knockout mice. Arterioscler Thromb Vasc Biol, 2009, 29(12): 2061-2068.
18. Zhang R, Yu Y, Deng J, et al. Sesamin ameliorates high-fat diet-induced dyslipidemia and kidney injury by reducing oxidative stress. Nutrients, 2016, 8(5):.
19. Osipov RM, Bianchi C, Feng J, et al. Effect of hypercholesterolemia on myocardial necrosis and apoptosis in the setting of ischemia-reperfusion. Circulation, 2009, 120(11 Suppl): S22-30.
20. Minville-Walz M, Gresti J, Pichon L, et al. Distinct regulation of stearoyl-CoA desaturase 1 gene expression by cis and trans C18: 1 fatty acids in human aortic smooth muscle cells. Genes Nutr, 2012, 7(2): 209-216.
21. 石志輝, 徐麟皓, 周銳. 牛磺熊去氧膽酸鈉抑制小鼠間歇性低氧模型肺組織中內質網應激的激活. 中南大學學報: 醫學版, 2015, 40(11): 1165-1172.
22. Shin C, Kim JK, Kim JH, et al. Increased cell-free DNA concentrations in patients with obstructive sleep apnea. Psychiatry Clin Neurosci, 2008, 62(6): 721-727.
23. 郝敏, 賈雪梅, 汪淵, 等. 高脂飲食大鼠腎組織中細胞凋亡及 Bcl-2 和 Bax 的表達. 安徽醫科大學學報, 2009, (2): 191-194.
24. 邱艷麗, 李巧稚, 鄭亞琴, 等. 內質網應激與氧化應激: 惡性循環還是雙刃劍?. 實用藥物與臨床, 2016, 19(8): 1037-1041.
25. Hetz C, Chevet E, Harding HP. Targeting the unfolded protein response in disease. Nat Rev Drug Discov, 2013, 12(9): 703-719.
26. Wang S, Kaufman RJ. The impact of the unfolded protein response on human disease. J Cell Biol, 2012, 197(7): 857-867.
27. Xu LH, Xie H, Shi ZH, et al. Critical role of endoplasmic reticulum stress in chronic intermittent hypoxia-induced deficits in synaptic plasticity and long-term memory. Antioxid Redox Signal, 2015, 23(9): 695-710.
28. Cai XH, Li XC, Jin SW, et al. Endoplasmic reticulum stress plays critical role in brain damage after chronic intermittent hypoxia in growing rats. Exp Neurol, 2014, 257: 148-156.
29. Sanchez AM, Martinez-Botas J, Malagarie-Cazenave S, et al. Induction of the endoplasmic reticulum stress protein GADD153/CHOP by capsaicin in prostate PC-3 cells: a microarray study. Biochem Biophys Res Commun, 2008, 372(4): 785-791.

Chinese Journal of Respiratory and Critical Care Medicine

Chronic intermittent hypoxia induces renal injury in rats by activating endoplasmic reticulum stress

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