• 1 濱州醫(yī)學(xué)院附屬醫(yī)院心內(nèi)科（山東濱州，256603）;2吉林大學(xué)第一醫(yī)院;

【摘要】　目的　 探討坎地沙坦干預(yù)后海仁藻酸（kainic acid，KA）致癇大鼠腎臟細(xì)胞外信號(hào)調(diào)節(jié)激酶（ERK1/2）的表達(dá)及其變化的機(jī)制。　方法　 105只雄性Wistar大鼠隨機(jī)分為3組:A1-5對(duì)照組、B1-5 致癇組、C1-5坎地沙坦組，每組各35只，1-5分別表示癲癇后0、2、6、12及24 h。采用立體定位儀下杏仁核內(nèi)注射KA方法制備大鼠癲癇模型，于致癇后不同時(shí)程，進(jìn)行灌流固定、腎臟組織的石蠟包埋、切片及免疫，組織化學(xué)染色，檢測(cè)不同時(shí)程腎臟ERK1/2表達(dá)的灰度值。　結(jié)果　 與對(duì)照組相比，致癇組及坎地沙坦組腎組織于致癇后2 h ERK1/2表達(dá)均開(kāi)始增加（致癇后2 h ERK1/2，致癲組：20 229.18±2 067.27，坎地沙坦組：16 878.19±2 693.97，對(duì)照組:8 054.24±975.90， P lt;0.01），致癇后6 h兩組大鼠腎組織ERK1/2的表達(dá)均達(dá)到高峰（致癇后6 h ERK1/2，致癇組:39 217.34±4 443.33，坎地沙坦組：31 924.85±4 383.80，對(duì)照組：8 575.24±1 040.82， P lt;0.01），隨后逐漸下降，致癇后24 h兩組大鼠腎組織ERK1/2表達(dá)均回到0 h水平（P gt;0.05），對(duì)致癇組及坎地沙坦干預(yù)兩組大鼠腎組織ERK1/2蛋白表達(dá)進(jìn)行組間比較結(jié)果顯示，坎地沙坦組2 h（致癇組：20 229.18±2 067.27，坎地沙坦組：16 878.19±2 693.97，P lt;0.01）、6 h（致癇組：39 217.34±4 443.33，坎地沙坦組：31 924.85±4 383.80，P lt;0.01）、12 h（致癇組：16 610.11±2 953.03，坎地沙坦組：13 393.16±2 269.42， P lt;0.05）ERK1/2表達(dá)降低。　結(jié)論　 ERK1/2在KA致癇大鼠腎組織中表現(xiàn)為短時(shí)程表達(dá)增加，坎地沙坦可使腎組織ERK1/2表達(dá)降低。
【Abstract】　Objective　 To study the effect of candesartan on extracellular signal-regulated kinase (ERK) 1/2 protein expression of renal cells in epilepsy rats induced by kainic acid (KA) and its mechanism.　Methods　 A total of 105 male Wistar rats were randomly divided into three groups: control group (A1-5, n=35), epilepsy group (B1-5, n=35), and candesartan group (C1-5, n=35). The sign 1-5 meant respectively 0, 2, 6, 12, and 24 hours after epilepsy. Epilepsy rat models were made by injecting KA into amygdala under three-dimensional positioning devices. Lavage fixation, paraffin embedding of the renal tissue, and immunohistological test were carried out at different time points after epilepsy was induced, and ERK1/2 protein expression level was tested.　Results　 Compared with the control group, the protein expression of ERK1/2 increased significantly 2 hours after epilepsy in groups B and C (ERK1/2 level 2 hours after epilepsy, group B: 20 229.18±2 067.27, group C: 16 878.19±2 693.97 vs. group A: 8 054.24±975.90, P＜0.01), and both attained its peak 6 hours after epilepsy (ERK1/2 level 6 hours after epilepsy, group B: 39 217.34±4 443.33, group C: 31 924.85±4 383.80 vs. group A: 8 575.24±1 040.82, P＜0.01), and then decreased gradually to the level immediately after epilepsy 24 hours later. There were significant differences in the level of ERK1/2 protein expression between group B and C 2, 6, and 12 hours after epilepsy was induced (2 hours, group B: 20 229.18±2 067.27 vs. group C: 16 878.19±2 693.97, P＜0.01; 6 hours, group B: 39 217.34±4 443.33 vs. group C: 31 924.85±4 383.80, P＜0.01; 12 hours, group B: 16 610.11±2 953.03 vs. group C: 13 393.16±2 269.42, P＜0.05).　Conclusions　 The Extracellular signal-regulated kinase1/2 protein expression of renal tissue in epilepsy rats induced by KA increases shortly after epilepsy. Candesartan can decrease the protein expression of ERK1/2 in the renal tissue of epilepsy rats.

引用本文： 馬寶新,吳綏生. 坎地沙坦干預(yù)海仁藻酸致癇大鼠腎臟細(xì)胞外信號(hào)調(diào)節(jié)激酶的表達(dá)及其機(jī)制. 華西醫(yī)學(xué), 2011, 26(7): 1014-1017. doi: 復(fù)制

1. 　孫小妹, 毛萌, 周暉, 等. 腦源性神經(jīng)營(yíng)養(yǎng)因子對(duì)缺氧胚腦皮質(zhì)神經(jīng)元發(fā)揮保護(hù)作用的細(xì)胞內(nèi)信號(hào)傳導(dǎo)機(jī)制[J]. 華西醫(yī)學(xué), 2006, 21(3): 454-456.
2. 　Li Y, Peng Z, Xiao B, et al. Activation of ERK by spontaneous seizures in neural progenitors of the dentate gyrus in a mouse model of epilepsy[J]. Exp Neurol, 2010, 224(1): 133-145.
3. 　Houser CR, Huang CS, Peng Z. Dynamic seizure-related changes in extracellular signal-regulated kinase activation in a mouse model of temporal lobe epilepsy[J]. Neuroscience, 2008, 156(1): 222-237.
4. 　楊小芳, 喻明, 聶本剛, 等. 單次癲癇發(fā)作后患者血清和腦脊液中神經(jīng)元特異性烯醇化酶及髓鞘堿性蛋白的變化[J]. 華西醫(yī)學(xué), 2010, 25(11): 2007-2008.
5. 　Tigaran S, Molgaard H, McClelland R, et al. Evidence of cardiac ischemia during seizures in drug refractory epilepsy patients[J]. Neurology, 2003, 60(3): 492-495.
6. 　Sakuragi S, Tokunaga N, Okawa K, et al. A case of takotsubo cardiomyopathy associated with epileptic seizure: reversible left ventricular wall motion abnormality and ST-segment elevation[J]. Heart Vessels, 2007, 22(1): 59-63.
7. 　Yatabe J, Sanada H, Yatabe MS, et al. Angiotensin II type 1 receptor blocker attenuates the activation of ERK and NADPH oxidase by mechanical strain in mesangial cells in the absence of angiotensin Ⅱ[J]. Am J Physiol Renal Physiol, 2009, 296(5): F1052-1060.
8. 　Feliers D, Kasinath BS. Mechanism of VEGF expression by high glucose in proximal tubule epithelial cells[J]. Mol Cell Endocrinol, 2010, 314(1): 136-142.
9. 　Zhou L, Xue H, Yuan P, et al. Angiotensin AT1 receptor activation mediates high glucose-induced epithelial-mesenchymal transition in renal proximal tubular cells[J]. Clin Exp Pharmacol Physiol, 2010, 37(9): e152-157.
10. 　Sekine S, Nitta K, Uchida K, et al. Possible involvement of mitogen-activated protein kinase in the angiotensin Ⅱ-induced fibronectin synthesis in renal interstitial fibroblasts[J]. Arch Biochem Biophys, 2003, 415(1): 63-68.
11. 　馬寶新, 吳綏生, 齊玲, 等. 氯沙坦對(duì)老年高血壓患者血液流變學(xué)和腎結(jié)構(gòu)的影響[J]. 中華高血壓雜志, 2007, 15(1): 70-71.
12. 　趙秀鶴, 遲兆富, 王勝軍, 等. ERK信號(hào)轉(zhuǎn)導(dǎo)通路在癲癇大鼠腦部作用的研究[J]. 神經(jīng)損傷與功能重建, 2006, 1(1): 14-16.
  1. 1. 　孫小妹, 毛萌, 周暉, 等. 腦源性神經(jīng)營(yíng)養(yǎng)因子對(duì)缺氧胚腦皮質(zhì)神經(jīng)元發(fā)揮保護(hù)作用的細(xì)胞內(nèi)信號(hào)傳導(dǎo)機(jī)制[J]. 華西醫(yī)學(xué), 2006, 21(3): 454-456.
  2. 2. 　Li Y, Peng Z, Xiao B, et al. Activation of ERK by spontaneous seizures in neural progenitors of the dentate gyrus in a mouse model of epilepsy[J]. Exp Neurol, 2010, 224(1): 133-145.
  3. 3. 　Houser CR, Huang CS, Peng Z. Dynamic seizure-related changes in extracellular signal-regulated kinase activation in a mouse model of temporal lobe epilepsy[J]. Neuroscience, 2008, 156(1): 222-237.
  4. 4. 　楊小芳, 喻明, 聶本剛, 等. 單次癲癇發(fā)作后患者血清和腦脊液中神經(jīng)元特異性烯醇化酶及髓鞘堿性蛋白的變化[J]. 華西醫(yī)學(xué), 2010, 25(11): 2007-2008.
  5. 5. 　Tigaran S, Molgaard H, McClelland R, et al. Evidence of cardiac ischemia during seizures in drug refractory epilepsy patients[J]. Neurology, 2003, 60(3): 492-495.
  6. 6. 　Sakuragi S, Tokunaga N, Okawa K, et al. A case of takotsubo cardiomyopathy associated with epileptic seizure: reversible left ventricular wall motion abnormality and ST-segment elevation[J]. Heart Vessels, 2007, 22(1): 59-63.
  7. 7. 　Yatabe J, Sanada H, Yatabe MS, et al. Angiotensin II type 1 receptor blocker attenuates the activation of ERK and NADPH oxidase by mechanical strain in mesangial cells in the absence of angiotensin Ⅱ[J]. Am J Physiol Renal Physiol, 2009, 296(5): F1052-1060.
  8. 8. 　Feliers D, Kasinath BS. Mechanism of VEGF expression by high glucose in proximal tubule epithelial cells[J]. Mol Cell Endocrinol, 2010, 314(1): 136-142.
  9. 9. 　Zhou L, Xue H, Yuan P, et al. Angiotensin AT1 receptor activation mediates high glucose-induced epithelial-mesenchymal transition in renal proximal tubular cells[J]. Clin Exp Pharmacol Physiol, 2010, 37(9): e152-157.
  10. 10. 　Sekine S, Nitta K, Uchida K, et al. Possible involvement of mitogen-activated protein kinase in the angiotensin Ⅱ-induced fibronectin synthesis in renal interstitial fibroblasts[J]. Arch Biochem Biophys, 2003, 415(1): 63-68.
  11. 11. 　馬寶新, 吳綏生, 齊玲, 等. 氯沙坦對(duì)老年高血壓患者血液流變學(xué)和腎結(jié)構(gòu)的影響[J]. 中華高血壓雜志, 2007, 15(1): 70-71.
  12. 12. 　趙秀鶴, 遲兆富, 王勝軍, 等. ERK信號(hào)轉(zhuǎn)導(dǎo)通路在癲癇大鼠腦部作用的研究[J]. 神經(jīng)損傷與功能重建, 2006, 1(1): 14-16.