Effect of Tasosartan on human renal tubular epithelial cells induced by glucose and oxygen deprivation and its mechanism
LIU Xiujuan1▲ WU Yu2 ZOU Xin1 YU Yanyan1 GENG Yanqiu3▲ SHUANG Feng4
1.Department of Nephrology, 908 Hospital of People’s Liberation Army Joint Logistic Support Forces, Jiangxi Province, Nanchang 330002, China;
2.Clinical Laboratory, 908 Hospital of People’s Liberation Army Joint Logistic Support Forces, Jiangxi Province, Nanchang 330002, China;
3.Department of Nephrology, the Third Medical Center of People’s Liberation Army General Hospital, Beijing 100039, China;
4.Department of Orthopedics, 908 Hospital of People’s Liberation Army Joint Logistic Support Forces, Jiangxi Province, Nanchang 330002, China
Abstract：Objective To investigate the effect of Tasosartan on human renal tubular epithelial cells (HK-2) induced by glucose and oxygen deprivation and its mechanism. Methods HK-2 cells were divided into control group (normal culture), glucose and oxygen deprivation group (glucose and oxygen deprivation culture) and Tasosartan group (glucose and oxygen deprivation cells were cultured with Tasosartan). MTT assay was used to detect cell proliferation, flow cytometry was used to detect cell apoptosis, Western blot analysis of α-smooth muscle actin (α-SMA), type Ⅰ collagen (Col Ⅰ), fibronectin (Fibronectin), E-cadherin (E-cadherin), glucose-regulated protein 78 (GRP78), C/EBP-homologous protein (CHOP), and toll-like receptor 4 (TLR4); meanwhile, the effect of TLR4 overexpression on HK-2 cells was detected. Results The cell proliferation rate in 15 μmol/L Tasosartan group was lower than that in glucose and oxygen deprivation group (P < 0.05). 10 μmol/L Tasosartan was selected as the concentration of glucose and oxygen deprivation HK-2 cells. The apoptosis rate of Tasosartan group was lower than that of glucose and oxygen deprivation group, the protein expression of α-SMA, Col Ⅰ and Fibronectin was lower than that of glucose and oxygen deprivation group, the protein expression of E-cadherin was higher than that of glucose and oxygen deprivation group, and the protein expression of GRP78 and CHOP were lower than those of glucose and oxygen deprivation group (P < 0.05). The expression of TLR4 in Tasosartan+ PCDNA3.1-TLR4 group was higher than that in Tasosartan group, and the apoptosis rate was higher than that in Tasosartan group, the protein expression of α-SMA, Col Ⅰ, Fibronectin, GRP78, and CHOP was higher than those in Tasosartan group, while the protein expression of E-cadherin was lower than that in Tasosartan group (P < 0.05). Conclusion Tasosartan can reduce endoplasmic reticulum stress in HK-2 cells cultured with glucose and oxygen deprivation, thereby attenuating the cell damage induced by glucose and oxygen deprivation, and its effect is produced by inhibiting TLR4.
刘秀娟1▲ 吴豫2 邹鑫1 余燕燕1 耿燕秋3▲ 双峰4. 他索沙坦对糖氧剥夺诱导人肾小管上皮细胞的影响及作用机制[J]. 中国医药导报, 2021, 18(31): 7-11.
LIU Xiujuan1▲ WU Yu2 ZOU Xin1 YU Yanyan1 GENG Yanqiu3▲ SHUANG Feng4. Effect of Tasosartan on human renal tubular epithelial cells induced by glucose and oxygen deprivation and its mechanism. 中国医药导报, 2021, 18(31): 7-11.
[1] Neutel JM，Buckalew V，Chrysant SG，et al. Efficacy and tolerability of tasosartan，a novel angiotensin Ⅱ receptor blocker：results from a 10-week，double-blind，placebo-controlled，dose-titration study. Tasosartan Investigators Group [J]. Am Heart J，1999，137（1）：118-125.
[2] Singh MV，Cicha MZ，Nunez S，et al. Angiotensin Ⅱ-induced hypertension and cardiac hypertrophy are differentially mediated by TLR3- and TLR4-dependent pathways [J]. Am J Physiol Heart Circ Physiol，2019，316（5）：H1027-H1038.
[3] Zhuang ZR，Wang ML，Peng YR，et al. Effect of C21 steroidal glycoside of Cynanchum auriculatum on liver and kidney fibrosis through TLR4 pathway [J]. Zhongguo Zhong Yao Za Zhi，2021，46（11）：2857-2864.
[4] Na SW，Jang YJ，Hong MH，et al. Protective Effect of Joa-Gui Em through the Improvement of the NLRP3 and TLR4/NF-kappab Signaling by Ischemia/Reperfusion-Induced Acute Renal Failure Rats [J]. Evid Based Complement Alternat Med，2021，5（28）：7178868.
[5] Tanaka T. A mechanistic link between renal ischemia and fibrosis [J]. Med Mol Morphol，2017，50（1）：1-8.
[6] Li ZL，Liu BC. Hypoxia and Renal Tubulointerstitial Fibrosis [J]. Adv Exp Med Biol，2019，1165（4）：67-85.
[7] Darby IA，Hewitson TD. Hypoxia in tissue repair and fibrosis [J]. Cell Tissue Res，2016，365（3）：553-562.
[8] 任广伟，龚淼，李明明，等.普罗布考对肾小管上皮细胞氧糖剥夺/复氧损伤的影响及其机制研究[J].中国医药科学，2019，22（18）：213-216.
[9] Xu S，Li Y，Chen JP，et al. Oxygen glucose deprivation/re-oxygenation-induced neuronal cell death is associated with Lnc-D63785 m6A methylation and miR-422a accumulation [J]. Cell Death Dis，2020，11（9）：816.
[10] Yin X，Feng L，Ma D，et al. Roles of astrocytic connexin-43，hemichannels，and gap junctions in oxygen-glucose deprivation/reperfusion injury induced neuroinflammation and the possible regulatory mechanisms of salvianolic acid B and carbenoxolone [J]. J Neuroinflammation，2018， 15（1）：97.
[11] 徐丹，周大燕，屈宗杰，等.血管紧张素Ⅱ受体阻滞剂剂量对高龄高血压合并慢性肾脏病3期患者的疗效及安全性的影响[J].中国医院药学杂志，2017，37（1）：62-64，72.
[12] Peluso AA，Santos RA，Unger T，et al. The angiotensin type 2 receptor and the kidney [J]. Curr Opin Nephrol Hypertens，2017，26（1）：36-42.
[13] 王玉浔，安雅臣，蒋艳茹，等.肾康注射液对腹膜纤维化小鼠E-cadherin和α-SMA动态表达的影响[J].中国新药杂志，2018，27（2）：195-202.
[14] Lebeaupin C，Vallee D，Hazari Y，et al. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease [J]. J Hepatol，2018，69（4）：927-947.
[15] Cybulsky AV. Endoplasmic reticulum stress，the unfolded protein response and autophagy in kidney diseases [J]. Nat Rev Nephrol，2017，13（11）：681-696.
[16] Yan M，Shu S，Guo C，et al. Endoplasmic reticulum stress in ischemic and nephrotoxic acute kidney injury [J]. Ann Med，2018，50（5）：381-390.
[17] Ibrahim IM，Abdelmalek DH，Elfiky AA. GRP78：A cell’s response to stress [J]. Life Sci，2019，226（1）：56-63.
[18] Sahin E，Bagci R，Bektur Aykanat NE，et al. Silymarin attenuated nonalcoholic fatty liver disease through the regulation of endoplasmic reticulum stress proteins GRP78 and XBP-1 in mice [J]. J Food Biochem，2020， 44（6）：e13194.
[19] Feng J，Chen Y，Lu B，et al. Autophagy activated via GRP78 to alleviate endoplasmic reticulum stress for cell survival in blue light-mediated damage of A2E-laden RPEs [J]. BMC Ophthalmol，2019，19（1）：249.
[20] Ardic S，Gumrukcu A，Gonenc Cekic O，et al. The value of endoplasmic reticulum stress markers（GRP78 and CHOP）in the diagnosis of acute mesenteric ischemia [J]. Am J Emerg Med，2019，37（4）：596-602.
[21] Hu H，Tian M，Ding C，et al. The C/EBP Homologous Protein（CHOP）Transcription Factor Functions in Endoplasmic Reticulum Stress-Induced Apoptosis and Microbial Infection [J]. Front Immunol，2018，4（9）：3083.
[22] Kamarehei M，Kabudanian Ardestani S，Firouzi M，et al. Increased expression of endoplasmic reticulum stress-related caspase-12 and CHOP in the hippocampus of EAE mice [J]. Brain Res Bull，2019，147（1）：174-182.
[23] Lv W，Booz GW，Wang Y，et al. Inflammation and renal fibrosis：Recent developments on key signaling molecules as potential therapeutic targets [J]. Eur J Pharmacol，2018，820：65-76.
[24] Souza AC，Tsuji T，Baranova IN，et al. TLR4 mutant mice are protected from renal fibrosis and chronic kidney disease progression [J]. Physiol Rep，2015，3（9）：e12558.
[25] Li R，Guo Y，Zhang Y，et al. Salidroside Ameliorates Renal Interstitial Fibrosis by Inhibiting the TLR4/NF-kappaB and MAPK Signaling Pathways [J]. Int J Mol Sci，2019，20（5）：1103.
京公网安备 11010502046598号