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- 2017
雌激素对大鼠肾缺血再灌注损伤后肾叶间动脉舒缩功能及Cx43表达的影响
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Abstract:
摘要：目的 研究雌激素(estrogen, E2)对大鼠肾缺血再灌注损伤后肾叶间动脉缝隙连接蛋白43(connexin43, Cx43)表达的影响。方法 建立SD大鼠肾缺血再灌注损伤模型，随机分为正常组、假手术组、缺血再灌注损伤组和E2干预组，于缺血再灌注损伤后24h检测肾功能变化；肾组织切片HE染色行Paller评分，量化肾损害程度。运用压力肌动技术检测各组大鼠肾叶间动脉的舒缩功能。免疫荧光技术、qRT-PCR及Western-blot检测各组大鼠肾叶间动脉Cx43表达的差异。 结果 E2能明显降低肾缺血再灌注损伤大鼠血清中血清肌酐(Cr)和尿素氮(BUN)水平，差异有统计学意义(P<0.05)，且能显著改善肾组织损害程度。肾缺血再灌注损伤后肾叶间动脉收缩率(24.80±3.70)%，给予E2干预后肾叶间动脉收缩率为(41.60±3.50)%，明显高于缺血再灌注损伤组，差异有统计学意义(P<0.05)。E2干预组肾叶间动脉上Cx43蛋白的表达水平明显低于缺血再灌注损伤组(P<0.01)。结论 E2能够下调缺血再灌注损伤后肾叶间动脉平滑肌细胞Cx43蛋白的表达，抑制缝隙连接(GJ)功能，从而降低血管紧张度，促进血管舒张，有效减轻肾缺血再灌注损伤，改善肾功能。
ABSTRACT: Objective?? To investigate the effect of estrogen (E2) on the connexin43 (Cx43) expression of renal interlobar arteries after renal ischemia-reperfusion injury (I/R). Methods??? The experiment was carried out in vivo using an SD rat I/R model. SD rats were randomly divided into normal group, sham-operation group, I/R group, and estrogen-intervention group. The functional changes of the kidney were analyzed after 24 hours of I/R; nephridial tissue section was stained by hematoxylin-eosin (HE), and Paller scores were used to evaluate the degree of kidney damage. Pressure myography was utilized to detect the vasomotor function of renal interlobar arteries. Immunofluorescence technique, qRT-PCR and Western blot were applied to determine the expression of Cx43 in renal interlobar arteries in different groups. Results?? ?Estrogen markedly decreased the levels of Cr and BUN in the serum of I/R rats (P<0.05), and the damage of the kidney tissue could be improved noticeably. The vasomotor rate of renal interlobar arteries was (24.80±3.70)% after I/R and (41.60±3.50)% after treatment with estrogen, which was higher than that of I/R group (P<0.05). The expression of Cx43 was lower in renal interlobar arteries of estrogen-intervention group than that in I/R group (P<0.01). Conclusion?? Estrogen may reduce vascular tension and boost dilation of the artery by inhibiting Cx43 expression and GJ function. Therefore, estrogen may attenuate the damage of I/R and improve renal function
| [1] | MENKE J, SOLLINGER D, SCHAMBERGER B, et al. The effect of ischemia/reperfusion on the kidney graft[J]. Curr Opin Organ Transplant, 2014, 19:395-400. |
| [2] | CHEN J, VEMURI C, PALEKAR RU, et al. Antithrombin nanoparticles improve kidney reperfusion and protect kidney function after ischemia-reperfusion injury[J]. Am J Physiol Renal Physiol, 2015, 308(7):765-773. |
| [3] | ABED AB, KAVVADAS P, CHADJICHRISTOS CE. Functional roles of connexins and pannexins in the kidney[J]. Cell Mol Life Sci, 2015, 72(15):2869-2877. |
| [4] | GUO JM, SHU H, WANG L, et al. SIRT1-dependent AMPK pathway in the protection of estrogen against ischemic brain injury[J]. CNS Neurosci Ther, 2017, 23(4):360-369. |
| [5] | FRANK A, BONNEY M, BONNEY S, et al. Myocardial ischemia reperfusion injury: from basic science to clinical bedside[J]. Semin Cardiothorac Vasc Anesth, 2012, 16(3):123-132. |
| [6] | ROVCANIN B, MEDIC B, KOCIC G, et al. Molecular dissection of renal ischemia-reperfusion: Oxidative stress and cellular events[J]. Curr Med Chem, 2016, 23(19):1965-1980. |
| [7] | PATSCHAN D,PATSCHAN S, M？aLLER GA.Inflammation and microvasculopathy in renal ischemia reperfusion injury[J]. J Transplant, 2011, (2012):1-7. |
| [8] | MATCHKOV VV. Mechanisms of cellular synchronization in the vascular wall. Mechanisms of vasomotion[J]. Dan Med Bull, 2010, 57(10):4191. |
| [9] | MILKAU M, K？ZHLER R, DE WIT C. Crucial importance of the endothelial K<sup>+</sup> channel SK3 and connexin40 in arteriolar dilations during skeletal muscle contraction[J]. FASEB J, 2010, 24(9):3572-3579. |
| [10] | 王智昊，吴扬，王英凯. 血管平滑肌细胞的增殖因素及机制[J]. 吉林大学学报(医学版), 2011, 37(3):561-566. |
| [11] | WANG WK, CHEN MC, LEONG HF, et al. Connexin 43 suppresses tumor angiogenesis by down-regulation of vascular endothelial growth factor via hypoxic-induced factor-1α[J]. Int J Mol Sci, 2014, 16(1):439-451. |
| [12] | BARNABAS O, WANG H, GAO XM. Role of estrogen in angiogenesis in cardiovascular diseases[J]. J Geriatr Cardiol, 2013, 10(4):377-382. |
| [13] | HAN XJ, HE D, XU LJ, et al. Knockdown of connexin 43 attenuates balloon injury-induced vascular restenosis through the inhibition of the proliferation and migration of vascular smooth muscle cells[J]. Int J Mol Med, 2015, 36(5):1361-1368. |
| [14] | MUNSHI R, HSU C, HIMMELFARB J. Advances in understanding ischemic acute kidney injury[J]. BMC Med, 2011, 9(1):1-6. |
| [15] | SEUL KH, BEYER EC. Heterogeneous localization of connexin40 in the renal vasculature[J]. Microvasc Res, 2000, 59(1):140-148. |
| [16] | KURTZ LI, MADSEN K, KURT B, et al. High-level connexin expression in the human juxtaglomerular apparatus[J]. Nephron Physiol, 2010, 116(1):1-8. |
| [17] | REN J, WANG XH, WANG GC, et al. 17-β estradiol regulation of connexin 43-based gap junction and mechanosensitivity through classical estrogen receptor pathway in osteocyte-like MLO-Y4 cells[J]. Bone, 2013, 53(2):587-596. |
| [18] | STAUFFER BL, SOBUS RD, SUCHAROV CC. Sex differences in cardiomyocyte connexin43 expression[J]. Cardiovasc Pharmacol, 2011, 58(1):32-39. |
| [19] | TONG D, LU X, WANG HX, et al. A dominant loss-of-function GJA1 (Cx43) mutant impairs parturition in the mouse[J]. Biol Reprod, 2009, 80(6):1099-1106. |
| [20] | GE YZ, WU R, XIN H, et al. Effects of ischemic preconditioning on the systemic and renal hemodynamic changes in renal ischemia reperfusion injury[J]. Int J Clin Exp Pathol, 2015, 8(2):1128-1140. |
| [21] | MIGITA H, YOSHITAKE S, TANGE Y, et al. Hyperbaric oxygen therapy suppresses apoptosis and promotes renal tubular regeneration after renal ischemia/reperfusion injury in rats[J]. Nephrourol Mon, 2016, 17(1):1-5. |
| [22] | 陈莉娜，王兴会，余玲，等. 缺血后处理对大鼠肾脏缺血/再灌注损伤的保护作用[J]. 西安交通大学学报(医学版), 2011, 32(6):684-686. |
| [23] | SCHULZ R, GORGE PM, GORBE A, et al. Connexin 43 is an emerging therapeutic target in ischemia/reperfusion injury, cardioprotection and neuroprotection[J]. Pharmacol Ther, 2015, 153:90-106. |
| [24] | LI DQ, CHEN WX, ZHOU YP, et al. Effect of ramipril on the regulation of the expression of connexins 40 and 43 in a rabbit model of arterial balloon injury[J]. Mol Med Rep, 2012, 6(3):565-569. |
