力竭运动致大鼠慢性肾损伤机制及促红细胞生成素干预研究
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摘要
目的：探讨力竭运动致大鼠慢性肾损伤机制及促红细胞生成素干预研究。
方法：采用反复四周力竭运动建立大鼠慢性肾损伤模型,用人重组促红细胞生成素(rhEPO)对此模型进行干预。光学显微镜HE染色观察肾组织病理改变；电镜检测肾组织超微结构；TUNEL检测肾细胞凋亡；用分子生物化学法检测大鼠血清尿素氮、MDA、SOD、NO、NOS、Hb含量、RBC计数、尿蛋白含量；免疫组化、荧光标记和Western blotting检测肾组织EPO/EPOR、Caspase-3、Bcl-xl、NF-κB、TGF-B1、a-SMA、JAK2、Akt的蛋白表达。
结果：
1.反复4周大强度力竭运动后大鼠体重、跑距、血清、Hb显著性下降(P<0.05),血清BUN、尿蛋白含量显著性增高(P<0.05),肾组织结构及超微结构明显病理改变。
2.反复四周力竭运动致慢性肾损伤后大鼠肾皮髓区的EPO和EPOR表达增强,与对照组比较,有统计学意义(P<0.05)。
3.应用rhEPO后,力竭大鼠一般状况明显改善,跑距明显延长,与对照组相比,血BUN及尿蛋白均明显降低(P<0.05),肾组织凋亡细胞明显减少(P<0.05),肾组织超微结构、病理损伤明显改善。
4.与正常对照组比较,rhEPO可明显升高NO、NOS活性及Bcl-xl、JAK2、Akt蛋白表达(P<0.05),显著拮抗NF-κB、TGF-B1、a-SMA、Caspase-3表达(P<0.05)。
结论：
1.反复4周大强度力竭运动可致大鼠慢性肾损伤。
2.反复4周力竭运动后,肾组织EPO/EPOR蛋白表达增加,提示内源性EPO/EPOR参与慢性肾损伤的内在修复机制。
3. rhEPO能减轻力竭运动致大鼠慢性肾组织病理损伤和改善肾功能的同时,明显提高大鼠的体能及运动能力。考虑rhEPO可通过抗氧化应激反应,升高NO、NOS活性,拮抗炎性核因子NF-κB表达,拮抗致纤维化因子TGF-B1、a-SMA表达和(或)减少肾组织细胞的凋亡而减轻力竭运动致慢性肾损伤。
4. rhEPO可以明显减少慢性肾损伤后凋亡细胞数量,可能与增加Bcl-xl、降低Caspase-3的表达而起到抗凋亡的作用。可能通过PI3K/Akt信号转导途径发挥保护作用。
Objects:The aims of present study were to investigate the protective effects and the mechanisms of Erythropoietin on the chronic kidney damage following 4 weeks exhausted movement in rats.
Methods:chronic renal damage model was established with 4 weeks exhaustion movement in rats, rhEPO intervened with this model. HE dying of histopathological changes of renal was detected with Optical microscope; electron microscopy examined pulp ultra structure of renal in rats; TUNEL tested renal cell apoptosis, testing rat serum urea nitrogen, MDA and SOD, NO, NOS, Hb content, RBC counting, urine protein content; with immunohistochemical, fluorescent marker and West-blot testing kidney tissues EPO EPOR, Caspase-3/ and Bcl-XL, NF-κB, TGF-B1, a-SMA, Akt JAK2, the protein expression.
Results:
1. After repeated 4 weeks exhaustion movement, compared with normal control group, the weight, ran distance, serum Hb in rats declined significantly (P<0.05), serum BUN, urinary protein content increased significantly (P<0.05), kidney organization structure and ultra structural obvious pathological changed.
2. After repeated 4 weeks exhaustion movement, compared with control group, the EPOR and EPO protein expression increased significantly in chronic renal injury (P< 0.05).
3. General condition improved obviously in exhausted rats after appling for rhEPO, extended running miles,compared with control, BUN,Hb and urine protein are obvious reduced (P< 0.05), the apoptotic cells of kidney tissues significantly reduced(P<0.05), kidney tissues ultra structure, pathological damage improved obviously.
4. Compared with normal control groups, rhEPO can obviously increases NO,NOS activity and Bcl-xl, JAK2, Akt protein expression (P< 0.05), significant antagonists inflammatory nuclear factor NF-KB, fibrosis factors-1, a-SMA, Caspase-3 express (P< 0.05).
Conclusion:
1. Repeated 4 weeks exhaustion movement can cause chronic renal injury in rats.
2. The model of chronic kidney damage, kidney tissues EPOR/EPOR protein expression increases, hinting endogenous EPOR/EPOR in chronic renal damage/the intrinsic repair mechanisms.
3. rhEPO can reduce chronic renal tissue injury induced by exhausted movement in rats and improve the morphological and renal function, obviously improving the sports ability. rhEPO has antioxidant stress response, elevates nitric oxide (NO), NOS activity, antagonists NF-κB, TGF, a-SMA expression and (or) reduces renal tissue cell apoptosis and reduces chronic renal injury.
4. rhEPO can significantly reduce chronic renal injury, may increase Bcl-XL expression, reduce Caspase-3 expression and play the role of antiapoptotic. In this model, EPO/EPOR may pass PI3K/Akt signal transduction pathways playing a protective role.
方法：采用反复四周力竭运动建立大鼠慢性肾损伤模型,用人重组促红细胞生成素(rhEPO)对此模型进行干预。光学显微镜HE染色观察肾组织病理改变；电镜检测肾组织超微结构；TUNEL检测肾细胞凋亡；用分子生物化学法检测大鼠血清尿素氮、MDA、SOD、NO、NOS、Hb含量、RBC计数、尿蛋白含量；免疫组化、荧光标记和Western blotting检测肾组织EPO/EPOR、Caspase-3、Bcl-xl、NF-κB、TGF-B1、a-SMA、JAK2、Akt的蛋白表达。
结果：
1.反复4周大强度力竭运动后大鼠体重、跑距、血清、Hb显著性下降(P<0.05),血清BUN、尿蛋白含量显著性增高(P<0.05),肾组织结构及超微结构明显病理改变。
2.反复四周力竭运动致慢性肾损伤后大鼠肾皮髓区的EPO和EPOR表达增强,与对照组比较,有统计学意义(P<0.05)。
3.应用rhEPO后,力竭大鼠一般状况明显改善,跑距明显延长,与对照组相比,血BUN及尿蛋白均明显降低(P<0.05),肾组织凋亡细胞明显减少(P<0.05),肾组织超微结构、病理损伤明显改善。
4.与正常对照组比较,rhEPO可明显升高NO、NOS活性及Bcl-xl、JAK2、Akt蛋白表达(P<0.05),显著拮抗NF-κB、TGF-B1、a-SMA、Caspase-3表达(P<0.05)。
结论：
1.反复4周大强度力竭运动可致大鼠慢性肾损伤。
2.反复4周力竭运动后,肾组织EPO/EPOR蛋白表达增加,提示内源性EPO/EPOR参与慢性肾损伤的内在修复机制。
3. rhEPO能减轻力竭运动致大鼠慢性肾组织病理损伤和改善肾功能的同时,明显提高大鼠的体能及运动能力。考虑rhEPO可通过抗氧化应激反应,升高NO、NOS活性,拮抗炎性核因子NF-κB表达,拮抗致纤维化因子TGF-B1、a-SMA表达和(或)减少肾组织细胞的凋亡而减轻力竭运动致慢性肾损伤。
4. rhEPO可以明显减少慢性肾损伤后凋亡细胞数量,可能与增加Bcl-xl、降低Caspase-3的表达而起到抗凋亡的作用。可能通过PI3K/Akt信号转导途径发挥保护作用。
Objects:The aims of present study were to investigate the protective effects and the mechanisms of Erythropoietin on the chronic kidney damage following 4 weeks exhausted movement in rats.
Methods:chronic renal damage model was established with 4 weeks exhaustion movement in rats, rhEPO intervened with this model. HE dying of histopathological changes of renal was detected with Optical microscope; electron microscopy examined pulp ultra structure of renal in rats; TUNEL tested renal cell apoptosis, testing rat serum urea nitrogen, MDA and SOD, NO, NOS, Hb content, RBC counting, urine protein content; with immunohistochemical, fluorescent marker and West-blot testing kidney tissues EPO EPOR, Caspase-3/ and Bcl-XL, NF-κB, TGF-B1, a-SMA, Akt JAK2, the protein expression.
Results:
1. After repeated 4 weeks exhaustion movement, compared with normal control group, the weight, ran distance, serum Hb in rats declined significantly (P<0.05), serum BUN, urinary protein content increased significantly (P<0.05), kidney organization structure and ultra structural obvious pathological changed.
2. After repeated 4 weeks exhaustion movement, compared with control group, the EPOR and EPO protein expression increased significantly in chronic renal injury (P< 0.05).
3. General condition improved obviously in exhausted rats after appling for rhEPO, extended running miles,compared with control, BUN,Hb and urine protein are obvious reduced (P< 0.05), the apoptotic cells of kidney tissues significantly reduced(P<0.05), kidney tissues ultra structure, pathological damage improved obviously.
4. Compared with normal control groups, rhEPO can obviously increases NO,NOS activity and Bcl-xl, JAK2, Akt protein expression (P< 0.05), significant antagonists inflammatory nuclear factor NF-KB, fibrosis factors-1, a-SMA, Caspase-3 express (P< 0.05).
Conclusion:
1. Repeated 4 weeks exhaustion movement can cause chronic renal injury in rats.
2. The model of chronic kidney damage, kidney tissues EPOR/EPOR protein expression increases, hinting endogenous EPOR/EPOR in chronic renal damage/the intrinsic repair mechanisms.
3. rhEPO can reduce chronic renal tissue injury induced by exhausted movement in rats and improve the morphological and renal function, obviously improving the sports ability. rhEPO has antioxidant stress response, elevates nitric oxide (NO), NOS activity, antagonists NF-κB, TGF, a-SMA expression and (or) reduces renal tissue cell apoptosis and reduces chronic renal injury.
4. rhEPO can significantly reduce chronic renal injury, may increase Bcl-XL expression, reduce Caspase-3 expression and play the role of antiapoptotic. In this model, EPO/EPOR may pass PI3K/Akt signal transduction pathways playing a protective role.
引文
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