芪卫颗粒对自发性2型糖尿病KK-Ay小鼠肾功能的影响及机制
|
摘要
目的观察芪卫颗粒对自发性2型糖尿病KK-Ay小鼠肾功能的影响及机制。方法 8周龄雄性KK-Ay小鼠高脂饲料喂养至12周制备糖尿病肾病模型,将造模成功的KK-Ay小鼠随机分为模型组、西药缬沙坦组、芪卫颗粒组,PERK抑制剂GSK2656157组各8只,并以C57BL/6J小鼠8只作为正常对照组。各组小鼠每日予相应药物灌胃。动态监测小鼠空腹血糖(FBG)、24 h尿微量白蛋白排泄率(UAER)。连续给药8周后,麻醉处死取血尿及肾组织,测定血尿素氮(BUN)及肌酐(SCr)含量,并取肾皮质行HE染色观察病理变化;Western blotting法检测肾组织内质网应激相关蛋白GRP78、PERK及P-PERK的表达。结果与模型组比较,芪卫颗粒组能明显减轻小鼠蛋白尿及改善肾功能(P<0.05),肾组织GRP78和P-PERK的蛋白表达明显下降(P<0.05),肾组织病理变化改善显著。结论芪卫颗粒可减少自发性2型糖尿病KK-Ay小鼠尿蛋白,改善其肾功能,其作用机制可能与抑制内质网应激PERK通路相关。
Objective To study the effects and the mechanism of Qiwei Granules on the expression of renal function in KK-Ay mice with spontaneous type 2 diabetes. Methods 8-week-old male KK-Ay mice were fed by research forage for 12 weeks to establish model with diabetic nephropathy,the model mice were randomly divided into model group,Valsartan group,Qi-wei Granules group,PERK inhibitor group with 8 mice in each group. 8 C57 BL/6 J mice were set up as the control group. All the mice received daily gavage administration with corresponding medicines. Fasting plasma glucose(FBG),24 h urinary excretion(UAER)were examined. At age of 20 weeks,bloody urine and kidney tissue were obtained after anaesthetic death to examine the renal function(BUN,SCr). The pathological morphology of renal tissue were observed by hemmatoxylin eosin(HE)stain,while the protein expressions of GRP78 and PERK were measured by western blot. Results Compared with the model group,albuminuria and renal function were alleviated in Qiwei Granules group(P<0.05),the protein level of GRP78 and PERK were significantly decreased(P<0.05). The pathological changes of kidney tissue were obviously improved. Conclusion QWG could reduce albuminuria and improve renal function in KK-Ay mice with spontaneous type 2 diabetes. The protective effect may be associated with inhibition of PERK signaling pathways.
Objective To study the effects and the mechanism of Qiwei Granules on the expression of renal function in KK-Ay mice with spontaneous type 2 diabetes. Methods 8-week-old male KK-Ay mice were fed by research forage for 12 weeks to establish model with diabetic nephropathy,the model mice were randomly divided into model group,Valsartan group,Qi-wei Granules group,PERK inhibitor group with 8 mice in each group. 8 C57 BL/6 J mice were set up as the control group. All the mice received daily gavage administration with corresponding medicines. Fasting plasma glucose(FBG),24 h urinary excretion(UAER)were examined. At age of 20 weeks,bloody urine and kidney tissue were obtained after anaesthetic death to examine the renal function(BUN,SCr). The pathological morphology of renal tissue were observed by hemmatoxylin eosin(HE)stain,while the protein expressions of GRP78 and PERK were measured by western blot. Results Compared with the model group,albuminuria and renal function were alleviated in Qiwei Granules group(P<0.05),the protein level of GRP78 and PERK were significantly decreased(P<0.05). The pathological changes of kidney tissue were obviously improved. Conclusion QWG could reduce albuminuria and improve renal function in KK-Ay mice with spontaneous type 2 diabetes. The protective effect may be associated with inhibition of PERK signaling pathways.
引文
[1] 章九红,李文泉,耿建国,等.加味消渴康治疗糖尿病肾病临床疗效观察[J].北京中医药,2015,34(1):6-9.
[2] 中华医学会糖尿病学分会.中国2型糖尿病防治指南(2013年版)[J].中华糖尿病杂志,2014,6(7):447-498.
[3] Ahmad J. Management of diabetic nephropathy: Recent progress and future perspective[J]. Diabetes Metab Syndr,2015,9(4):343-358.
[4] National Kidney Foundation. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 update[J]. Am J Kidney Dis,2012,60(5):850-886.
[5] 李步满,高彦彬,吴丽丽,等.中药芪卫颗粒对2型糖尿病大鼠肾脏氧化应激及病理改变的影响[J].中国中西医结合肾病,2011,12(1):20-23.
[6] 王馨瑶,耿建国,高彦彬,等.芪卫颗粒对DN大鼠足细胞Nephrin表达影响的实验研究[J],环球中医药,2015,2(2):141-144.
[7] 马鸣飞,高彦彬,王金羊,等.芪卫颗粒调节KK Ay小鼠肾组织USF2表达对肾纤维化的干预研究[J].疑难病杂志,2013,12(1):41-45.
[8] Wang J,Gao Y,Ma M,et al. Effect of miR-21 on Renal Fibrosis by Regulating MMP-9 and TIMP1 in kk-ay Diabetic Nephropathy Mice[J]. Cell Biochem Biophys,2013,67(2):537-546.
[9] Zhang N,Gao YB,Zou DW,et al. Effects of Chinese Medicine Tong xinluo on Diabetic Nephropathy via Inhibiting TGF-β1-Induced Epithelial-to-Mesenchymal Transition[J]. Evidence-Based Complementary and Alternative Medicine,2014,2014(2014):123497.
[10] 高彦彬,赵慧玲,周晖.糖肾宁治疗糖尿病肾病的研究[J].中华中医药杂志,2006,21(7):409-411.
[11] 彭继升,高彦彬.芪卫颗粒治疗早期糖尿病肾病的临床研究[D].北京:北京中医药大学,2007.
[12] 高彦彬,刘铜华.止消通脉宁治疗糖尿病肾病临床及作用机制研究[C]. 广州:中华医学会第六次全国内分泌学术会议,2001.
[13] 李步满,高彦彬,吴丽丽,等.中药芪卫颗粒对2型糖尿病大鼠肾脏氧化应激及病理改变的影响[J].中国中西医结合肾病杂志,2011,12(1):20-23.
[14] 王馨瑶,耿建国,高彦彬,等.芪卫颗粒对糖尿病肾病大鼠足细胞CD2AP表达的影响[J].首都医科大学学报,2015,36(2):1-5.
[15] Shen J,Chen X,Hendershot L,et al. ER stess regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals[J]. Dev cell,2002,3(1):99-111.
[16] Szegezdi E,Logue SE,Gorman AM,et al. Mediators of endoplasmic reticulum stress-induced apoptosis[J]. EMBO Rep,2006,7(9):880-885.
[17] Qi W,Mu J,Luo ZF,et al. Attenuation of diabetic nephropathy in diabetes rats induced by streptozotocin by regulating the endoplasmic reticulum stress inflammatory response[J]. Metabolism,2011,60(5):594-603.
[18] EI Karoui K,Viau A,Dellis O,et al. Endoplasmic reticulum stress drives proteinuria-induced kidney lesions via Lipocalin 2[J]. Nat Commun,2016,7:10330.
[19] Atkins C,Liu Q,Minthorn E,et al. Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity [J]. Cancer Res,2013,73(6):1993-2002.
[2] 中华医学会糖尿病学分会.中国2型糖尿病防治指南(2013年版)[J].中华糖尿病杂志,2014,6(7):447-498.
[3] Ahmad J. Management of diabetic nephropathy: Recent progress and future perspective[J]. Diabetes Metab Syndr,2015,9(4):343-358.
[4] National Kidney Foundation. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 update[J]. Am J Kidney Dis,2012,60(5):850-886.
[5] 李步满,高彦彬,吴丽丽,等.中药芪卫颗粒对2型糖尿病大鼠肾脏氧化应激及病理改变的影响[J].中国中西医结合肾病,2011,12(1):20-23.
[6] 王馨瑶,耿建国,高彦彬,等.芪卫颗粒对DN大鼠足细胞Nephrin表达影响的实验研究[J],环球中医药,2015,2(2):141-144.
[7] 马鸣飞,高彦彬,王金羊,等.芪卫颗粒调节KK Ay小鼠肾组织USF2表达对肾纤维化的干预研究[J].疑难病杂志,2013,12(1):41-45.
[8] Wang J,Gao Y,Ma M,et al. Effect of miR-21 on Renal Fibrosis by Regulating MMP-9 and TIMP1 in kk-ay Diabetic Nephropathy Mice[J]. Cell Biochem Biophys,2013,67(2):537-546.
[9] Zhang N,Gao YB,Zou DW,et al. Effects of Chinese Medicine Tong xinluo on Diabetic Nephropathy via Inhibiting TGF-β1-Induced Epithelial-to-Mesenchymal Transition[J]. Evidence-Based Complementary and Alternative Medicine,2014,2014(2014):123497.
[10] 高彦彬,赵慧玲,周晖.糖肾宁治疗糖尿病肾病的研究[J].中华中医药杂志,2006,21(7):409-411.
[11] 彭继升,高彦彬.芪卫颗粒治疗早期糖尿病肾病的临床研究[D].北京:北京中医药大学,2007.
[12] 高彦彬,刘铜华.止消通脉宁治疗糖尿病肾病临床及作用机制研究[C]. 广州:中华医学会第六次全国内分泌学术会议,2001.
[13] 李步满,高彦彬,吴丽丽,等.中药芪卫颗粒对2型糖尿病大鼠肾脏氧化应激及病理改变的影响[J].中国中西医结合肾病杂志,2011,12(1):20-23.
[14] 王馨瑶,耿建国,高彦彬,等.芪卫颗粒对糖尿病肾病大鼠足细胞CD2AP表达的影响[J].首都医科大学学报,2015,36(2):1-5.
[15] Shen J,Chen X,Hendershot L,et al. ER stess regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals[J]. Dev cell,2002,3(1):99-111.
[16] Szegezdi E,Logue SE,Gorman AM,et al. Mediators of endoplasmic reticulum stress-induced apoptosis[J]. EMBO Rep,2006,7(9):880-885.
[17] Qi W,Mu J,Luo ZF,et al. Attenuation of diabetic nephropathy in diabetes rats induced by streptozotocin by regulating the endoplasmic reticulum stress inflammatory response[J]. Metabolism,2011,60(5):594-603.
[18] EI Karoui K,Viau A,Dellis O,et al. Endoplasmic reticulum stress drives proteinuria-induced kidney lesions via Lipocalin 2[J]. Nat Commun,2016,7:10330.
[19] Atkins C,Liu Q,Minthorn E,et al. Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity [J]. Cancer Res,2013,73(6):1993-2002.