肾气丸对庆大霉素诱导大鼠耳肾损伤模型Notch2/hes1信号通路的影响及机制
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摘要
目的：肾气丸对庆大霉素诱导大鼠耳肾损伤模型Notch2/hes1信号通路的影响及机制。
方法：成熟SD大鼠随机分成空白组、模型组、DAPT组、肾气丸组。采用庆大霉素(120mg/(kg.d),腹腔注射,持继10天)造模。在造模前及造模后1、14、28天,应用听觉脑干诱发电位(ABR)检测听力变化；应用耳蜗铺片观察耳蜗毛细胞损伤及修复情况。应用光镜和电镜观察肾小管损伤情况及药后恢复情况。应用免疫荧光观察表达耳肾Ki67阳性细胞的情况；免疫组化观察Jag2/Notch2/hes1信号在肾小管表达情况；应用免疫印迹蛋白、实时定量PCR观察大鼠Jag2/Notch2/hes1信号通路在造模后1、14、28天在耳蜗和肾组织表达情况。
结果：肾脏检测结果：病理检测：在空白组,各时段的肾小管没有明显变化。模型组,在第1天,肾小管受到严重损伤；14天,肾小管损伤明显减轻；28天,肾小管基本恢复正常；在第1、14天,与模型组相比,DAPT组造成的肾脏损伤程度明显减轻；在28天,模型组和DAPT组肾小管基本恢复正常。在第1、14天,与模型组相比,肾气丸组的肾脏损伤程度明显减轻；在第28天,肾气丸组和模型组肾小管基本恢复正常。免疫组化、免疫印迹蛋白、RT-PCR显示：模型组造模后1、14天,Jag2/Notch2/hes1在肾小管上皮细胞的表达明显升高(P<0.05)；在第28天,与空白组相比表达无明显差异(P>0.05)。在第1、14天,DAPT组与模型组相比Jag2/Notch2/hes1的表达明显下降(P<0.05)；在第28天,两组表达无明显差异(P>0.05)；在DAPT组内,第28天与第1、14天相比,Jag2/Notch2/hes1的表达明显下降(P<0.05)。造模后1、14天,肾气丸组Jag2/Notch2/hes1在肾小管上皮细胞的表达与模型组相比明显下降(P<0.05)；在第28天,两组表达无明显差异(P>0.05)；在肾气丸组内,第28天与第1、14天相比,Jag2/Notch2/hes1的表达明显下降(P<0.05)。免疫荧光显示：在空白组,Ki67阳性表达细胞占2.52%；在模型组,造模后第1、14天,Ki67阳性表达细胞与空白组相比明显升高；在28天,空白组与模型组无明显差异。DAPT和肾气丸组与模型组相比,第1、14天,Ki67阳性表达细胞明显升高；在28天,肾气丸组和DAPT组与模型组无明显差异。
耳检测结果：听觉脑干诱发电位(ABR)显示：空白组无明显变化；模型组与用药前ABR阈值相比明显升高,并随时间的延长阈值下降。DAPT组和肾气丸组ABR阈值与用药前相比均明显升高,并随时间的延长阈值下降(P<0.05)；在造模后第28天,DAPT组与模型组相比ABR阈值明显下降；在造模后第28天,肾气丸组与模型组相比ABR阈值明显下降。耳蜗铺片显示：造模后1、14、28天,模型组与空白组相比毛细胞明显损伤；在模型组,毛细胞的损伤程度在28天时段明显减轻。在造模后1、14、28天,DAPT组与模型组相比毛细胞损伤明显减轻；在DAPT组,造模后28天与第1天相比,毛细胞损伤明显减轻。在造模后1、14、28天,肾气丸组与模型组相比毛细胞损伤明显减轻；在肾气丸组,造模后28天与第1天相比,毛细胞损伤明显减轻。免疫印迹蛋白、实时定量PCR显示：与空白组相比,模型组Jag2/Notch2/hes1的表达明显增高(P<0.05),并随时间的延长,表达强度下降。同时段的DAPT组与模型组相比Jag2/Notch2/hes1的表达明显下降(P<0.05); DAPT组内,第28天与第1天相比,Jag2/Notch2/hes1的表达明显下降(P<0.05)。同时段的肾气丸组与模型组相比,Jag2/Notch2/hes1的表达均明显下降(P<0.05)；在肾气丸组内,第28天与第1天相比,Jag2/Notch2/hes1的表达明显下降(P<0.05)。免疫荧光显示：免疫荧光显示：在空白组Ki67阳性表达细胞占1.42%；在模型组,造模后第1、14、28天,Ki67阳性表达细胞明显升高；DAPT组和肾气丸组与模型组相比,在相同时段的Ki67阳性表达细胞明显升高。
结论：Jag2/Notch2/hes1信号通路可能是庆大霉素诱导耳肾损伤及修复过程中的重要角色之一。DAPT和肾气丸可能通过抑制Jag2/Notch2/hesl信号通路,减轻肾间质小管上皮细胞和耳蜗毛细胞的损伤,并促进肾间质小管上皮细胞和耳蜗毛细胞的修复。
Purpose:The effect and mechanisms of Shenqi pill to Notch2/hesl Signaling Pathway in gentamicin-induced the rat-oto-renal injury model
Methods:The mature SD rats were randomly divided into normal group, model group, DAPT group, Shenqi pill group. We use Gentamicin model ing (120mg/(kg·d), intraperitoneal injection, continuous ten days). Before modeling and the1st,14th,28th day post-modeling,to detect hearing changes by auditory brainstem response (ABR); To observe the cochlea hair cell damage and repair with cochlea stretched. To observe the damage situation of renal tubules with light microscope and electron microscopy. To observe the percentage of Ki67-positive cells in oto-renal by immunofluorescence. Immunohistochemistry observed the expression of Jag2/Notch2/hesl signal in the tubular. By western-blotting and real-time quantitative PCR, observed expression of the Jag2/Notch2/hesl in cochlea and in kidney tissue in the1st,14th,28th post-modeling.
Results:Renal biopsy showed:In the normal group, the tubular no significant change in each time. In Model group, injury of the renal tubular is severe in the1st post-modeling; it is mitigation in the14th; the damage of tubular return to normal in the28th; in the1st14th, compared with the model group, the degree of kidney damage is obvious mitigation in the DAPT group; in the28th, tubular back to normal in DAPT. In the1st14th, compared with the model group, the degree of kidney damage is obvious mitigation in the Shenqi pill group; in the28th, tubular back to normal in the Shenqi pill. Immunohistochemistry, Western blot protein, real-time quantitative PCR show that the model group compared with the normal group, the level of Jag2/Notch2/hes1is significantly higher in the1st,14th (P<0.05); there is no significant difference in the28th (P>0.05); compared with the the model group, the level of Jag2/Notch2/hes1is significantly decrease in DAPT group (P<0.05); in the28th there is no significant difference between the model group and DAPT group (P>0.05). Compared with1st,14th, the Jag2/Notch2/hes1expression decreased (P<0.05) in the DAPT group in the28th. In the1st,14th, compared with the model group, the level of Jag2/Notch2/hes1is significantly decrease in the Shenqi pill group (P<0.05); in the28th, there is no significant difference between the model group and the Shenqi pill group (P>0.05); Compared with1st,14th, the Jag2/Notch2/hes1expression decreased (P<0.05) in the Shenqi pill group in the28th. Immunof luorescence showed:the percentage of Ki67-positive cells was2.52%in the normal group; Compared with the the normal group, the percentage of Ki67-positive cells was significant increased in the model group in the1st,14th. Compared with the the model group, the percentage of Ki67-positive cells was significant increased in the DAPT group and the Shenqi pill group in the1st,14th.
Auditory brainstem response (ABR) shows:the normal group had no significant change; compared with before treatment, the ABR threshold were significantly higher in model and DAPT and Shenqi group. Compared with model group, the ABR threshold is a significantly downward in the DAPT group. Compared with the model group, the ABR threshold were significantly decreased in Shenqi pill group. Cochlea shtreched show:damage of hair cell is severe in cochlea in the1st14th,28th after modeling in gentamicin group; and compared with the1st, hair cell damage is significantly reduced in the28th. Compared with the model group, damage of hair cell is reduced in the1st,14th,28th after modeling in DAPT group. Compared with the1st, hair cell damage is significantly reduced in the28th in the DAPT group. Compared with the model group, damage of hair cell is reduced in the1st14th,28th after modeling in the Shenqi pill group; and compared with the1st, hair cell damage is significantly reduced in the28th in the Shenqi pill group. Real-time quantitative PCR and western-blotting shows:compared with the normal group, the expression level of Jag2/Notch2/hesl is significantly higher in the1st,14th,28th in the model group (P<0.05); compared with the1st, the level of Jag2/Notch2/hesl is significantly downward in the28th in the model group (P<0.05). At the same time period compared with the model group, the expression level of Jag2/Notch2/hesl is significantly lower in DAPT group (P <0.05); compared with the1st, the expression level of Jag2/Notch2/hesl had evident decline in the28th in the DAPT group (P<0.05). At the same time period compared with the model group, the expression level of Jag2/Notch2/hesl is significantly lower in the Shenqi pill group (P<0.05); compared with the1st, the expression level of Jag2/Notch2/hes1had evident decline in the28th in the Shenqi pill group (P <0.05). Immunofluorescence showed:The percentage of Ki67-positive cells was1.42%in the normal group; Compared with the the normal group, the percentage of Ki67-positive cells was significant increased in the model group in the1st,14th,28th. Compared with the the model group, the percentage of Ki67-positive cells was significant increased in the DAPT group and the Shenqi pill group in the1st,14th,28th.
Conclusion:Jag2/Notch2/hes1signaling pathways may be one of the important role in the gentamicin-induced renal and ear injury and repair process. Shenqi pill and DAPT may be go through inhibit Jag2/Notch2/hes1signaling pathways to reduce ear and renal injury and promote tubular epithelial cell and the hair cells repair.
方法：成熟SD大鼠随机分成空白组、模型组、DAPT组、肾气丸组。采用庆大霉素(120mg/(kg.d),腹腔注射,持继10天)造模。在造模前及造模后1、14、28天,应用听觉脑干诱发电位(ABR)检测听力变化；应用耳蜗铺片观察耳蜗毛细胞损伤及修复情况。应用光镜和电镜观察肾小管损伤情况及药后恢复情况。应用免疫荧光观察表达耳肾Ki67阳性细胞的情况；免疫组化观察Jag2/Notch2/hes1信号在肾小管表达情况；应用免疫印迹蛋白、实时定量PCR观察大鼠Jag2/Notch2/hes1信号通路在造模后1、14、28天在耳蜗和肾组织表达情况。
结果：肾脏检测结果：病理检测：在空白组,各时段的肾小管没有明显变化。模型组,在第1天,肾小管受到严重损伤；14天,肾小管损伤明显减轻；28天,肾小管基本恢复正常；在第1、14天,与模型组相比,DAPT组造成的肾脏损伤程度明显减轻；在28天,模型组和DAPT组肾小管基本恢复正常。在第1、14天,与模型组相比,肾气丸组的肾脏损伤程度明显减轻；在第28天,肾气丸组和模型组肾小管基本恢复正常。免疫组化、免疫印迹蛋白、RT-PCR显示：模型组造模后1、14天,Jag2/Notch2/hes1在肾小管上皮细胞的表达明显升高(P<0.05)；在第28天,与空白组相比表达无明显差异(P>0.05)。在第1、14天,DAPT组与模型组相比Jag2/Notch2/hes1的表达明显下降(P<0.05)；在第28天,两组表达无明显差异(P>0.05)；在DAPT组内,第28天与第1、14天相比,Jag2/Notch2/hes1的表达明显下降(P<0.05)。造模后1、14天,肾气丸组Jag2/Notch2/hes1在肾小管上皮细胞的表达与模型组相比明显下降(P<0.05)；在第28天,两组表达无明显差异(P>0.05)；在肾气丸组内,第28天与第1、14天相比,Jag2/Notch2/hes1的表达明显下降(P<0.05)。免疫荧光显示：在空白组,Ki67阳性表达细胞占2.52%；在模型组,造模后第1、14天,Ki67阳性表达细胞与空白组相比明显升高；在28天,空白组与模型组无明显差异。DAPT和肾气丸组与模型组相比,第1、14天,Ki67阳性表达细胞明显升高；在28天,肾气丸组和DAPT组与模型组无明显差异。
耳检测结果：听觉脑干诱发电位(ABR)显示：空白组无明显变化；模型组与用药前ABR阈值相比明显升高,并随时间的延长阈值下降。DAPT组和肾气丸组ABR阈值与用药前相比均明显升高,并随时间的延长阈值下降(P<0.05)；在造模后第28天,DAPT组与模型组相比ABR阈值明显下降；在造模后第28天,肾气丸组与模型组相比ABR阈值明显下降。耳蜗铺片显示：造模后1、14、28天,模型组与空白组相比毛细胞明显损伤；在模型组,毛细胞的损伤程度在28天时段明显减轻。在造模后1、14、28天,DAPT组与模型组相比毛细胞损伤明显减轻；在DAPT组,造模后28天与第1天相比,毛细胞损伤明显减轻。在造模后1、14、28天,肾气丸组与模型组相比毛细胞损伤明显减轻；在肾气丸组,造模后28天与第1天相比,毛细胞损伤明显减轻。免疫印迹蛋白、实时定量PCR显示：与空白组相比,模型组Jag2/Notch2/hes1的表达明显增高(P<0.05),并随时间的延长,表达强度下降。同时段的DAPT组与模型组相比Jag2/Notch2/hes1的表达明显下降(P<0.05); DAPT组内,第28天与第1天相比,Jag2/Notch2/hes1的表达明显下降(P<0.05)。同时段的肾气丸组与模型组相比,Jag2/Notch2/hes1的表达均明显下降(P<0.05)；在肾气丸组内,第28天与第1天相比,Jag2/Notch2/hes1的表达明显下降(P<0.05)。免疫荧光显示：免疫荧光显示：在空白组Ki67阳性表达细胞占1.42%；在模型组,造模后第1、14、28天,Ki67阳性表达细胞明显升高；DAPT组和肾气丸组与模型组相比,在相同时段的Ki67阳性表达细胞明显升高。
结论：Jag2/Notch2/hes1信号通路可能是庆大霉素诱导耳肾损伤及修复过程中的重要角色之一。DAPT和肾气丸可能通过抑制Jag2/Notch2/hesl信号通路,减轻肾间质小管上皮细胞和耳蜗毛细胞的损伤,并促进肾间质小管上皮细胞和耳蜗毛细胞的修复。
Purpose:The effect and mechanisms of Shenqi pill to Notch2/hesl Signaling Pathway in gentamicin-induced the rat-oto-renal injury model
Methods:The mature SD rats were randomly divided into normal group, model group, DAPT group, Shenqi pill group. We use Gentamicin model ing (120mg/(kg·d), intraperitoneal injection, continuous ten days). Before modeling and the1st,14th,28th day post-modeling,to detect hearing changes by auditory brainstem response (ABR); To observe the cochlea hair cell damage and repair with cochlea stretched. To observe the damage situation of renal tubules with light microscope and electron microscopy. To observe the percentage of Ki67-positive cells in oto-renal by immunofluorescence. Immunohistochemistry observed the expression of Jag2/Notch2/hesl signal in the tubular. By western-blotting and real-time quantitative PCR, observed expression of the Jag2/Notch2/hesl in cochlea and in kidney tissue in the1st,14th,28th post-modeling.
Results:Renal biopsy showed:In the normal group, the tubular no significant change in each time. In Model group, injury of the renal tubular is severe in the1st post-modeling; it is mitigation in the14th; the damage of tubular return to normal in the28th; in the1st14th, compared with the model group, the degree of kidney damage is obvious mitigation in the DAPT group; in the28th, tubular back to normal in DAPT. In the1st14th, compared with the model group, the degree of kidney damage is obvious mitigation in the Shenqi pill group; in the28th, tubular back to normal in the Shenqi pill. Immunohistochemistry, Western blot protein, real-time quantitative PCR show that the model group compared with the normal group, the level of Jag2/Notch2/hes1is significantly higher in the1st,14th (P<0.05); there is no significant difference in the28th (P>0.05); compared with the the model group, the level of Jag2/Notch2/hes1is significantly decrease in DAPT group (P<0.05); in the28th there is no significant difference between the model group and DAPT group (P>0.05). Compared with1st,14th, the Jag2/Notch2/hes1expression decreased (P<0.05) in the DAPT group in the28th. In the1st,14th, compared with the model group, the level of Jag2/Notch2/hes1is significantly decrease in the Shenqi pill group (P<0.05); in the28th, there is no significant difference between the model group and the Shenqi pill group (P>0.05); Compared with1st,14th, the Jag2/Notch2/hes1expression decreased (P<0.05) in the Shenqi pill group in the28th. Immunof luorescence showed:the percentage of Ki67-positive cells was2.52%in the normal group; Compared with the the normal group, the percentage of Ki67-positive cells was significant increased in the model group in the1st,14th. Compared with the the model group, the percentage of Ki67-positive cells was significant increased in the DAPT group and the Shenqi pill group in the1st,14th.
Auditory brainstem response (ABR) shows:the normal group had no significant change; compared with before treatment, the ABR threshold were significantly higher in model and DAPT and Shenqi group. Compared with model group, the ABR threshold is a significantly downward in the DAPT group. Compared with the model group, the ABR threshold were significantly decreased in Shenqi pill group. Cochlea shtreched show:damage of hair cell is severe in cochlea in the1st14th,28th after modeling in gentamicin group; and compared with the1st, hair cell damage is significantly reduced in the28th. Compared with the model group, damage of hair cell is reduced in the1st,14th,28th after modeling in DAPT group. Compared with the1st, hair cell damage is significantly reduced in the28th in the DAPT group. Compared with the model group, damage of hair cell is reduced in the1st14th,28th after modeling in the Shenqi pill group; and compared with the1st, hair cell damage is significantly reduced in the28th in the Shenqi pill group. Real-time quantitative PCR and western-blotting shows:compared with the normal group, the expression level of Jag2/Notch2/hesl is significantly higher in the1st,14th,28th in the model group (P<0.05); compared with the1st, the level of Jag2/Notch2/hesl is significantly downward in the28th in the model group (P<0.05). At the same time period compared with the model group, the expression level of Jag2/Notch2/hesl is significantly lower in DAPT group (P <0.05); compared with the1st, the expression level of Jag2/Notch2/hesl had evident decline in the28th in the DAPT group (P<0.05). At the same time period compared with the model group, the expression level of Jag2/Notch2/hesl is significantly lower in the Shenqi pill group (P<0.05); compared with the1st, the expression level of Jag2/Notch2/hes1had evident decline in the28th in the Shenqi pill group (P <0.05). Immunofluorescence showed:The percentage of Ki67-positive cells was1.42%in the normal group; Compared with the the normal group, the percentage of Ki67-positive cells was significant increased in the model group in the1st,14th,28th. Compared with the the model group, the percentage of Ki67-positive cells was significant increased in the DAPT group and the Shenqi pill group in the1st,14th,28th.
Conclusion:Jag2/Notch2/hes1signaling pathways may be one of the important role in the gentamicin-induced renal and ear injury and repair process. Shenqi pill and DAPT may be go through inhibit Jag2/Notch2/hes1signaling pathways to reduce ear and renal injury and promote tubular epithelial cell and the hair cells repair.
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[9]Kopan R, Cagan R. Notch on the cutting edge. Trends Genet.1997; 13:465-467.
[10]Cheng HT, Kopan R. The role of Notch signaling in specification of podocyte and proximal tubules within the developing mouse kidney. Kidney Int.2005; 68:1951-1952. [PubMed:16221173]
[11]Cheng HT, Kim M, Valerius MT, et al. Notch2, but not Notchl, is required for proximal fate acquisition in the mammalian nephron. Development.2007; 134:801-811. [PubMed: 17229764]
[12]Niran jan T, Bielesz B, Gruenwald A, et al. The Notch pathway in podocytes plays a role in the development of glomerular disease. Nat Med.2008; 14:290-298. [PubMed:18311147]
[13]Vooijs M, Ong CT, Hadland B, et al. Mapping the consequence of Notchl proteolysis in vivo with NIP-CRE. Development. 2007; 134:535-544. [PubMed:17215306]
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[17]Huang R, Zhou Q, Veeraragoo P, Yu H, Xiao Z. Notch2/Hes-1 pathway plays an important role in renal ischemia and reperfusion injury-associated inflammation and apoptosis and the gamma-secretase inhibitor DAPT has a nephroprot-ective effect. Ren Fail.2011.33(2):207-16.
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[19]Kiernan AE, Xu J, Gridley T. The Notch ligand JAG1 is required for sensory progenitor development in the mammalian inner ear. PLoS Genet 2006; 2:27-38 [PubMed: 16410827]
[20]Daudet N, Ariza-McNaughton L, Lewis J. Notch signalling is needed to maintain, but not to initiate, the formation of prosensory patches in the chick inner ear. Dev 2007; 134:2369-2378. [PubMed:17537801]
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[23]Lanford PJ, Lan Y, Jiang R, Lindsell C, Weinmaster G, Gridley T, Kelley MW. Notch signalling pathway mediates hair cell development in mammalian cochlea. Nat Genet 1999; 21:289-292. [PubMed:10080181]
[24]Morrison A, Hodgetts C, Gossler A, Hrabe de Angel is M, Lewis J. Expression of Deltal and Serratel (Jaggedl) in the mouse inner ear. Mech Dev 1999; 84:169-172. [PubMed:10473135]
[25]Kiernan A, Cordes R, Kopan R, Gossler A, Gridley T. The Notch ligands DLL1 and JAG2 act synergistically to regulate hair cell development in the mammalian inner ear. Development 2005b; 132:4353-4362. [PubMed:16141228]
[26]Slattery EL, Warchol ME. Cisplatin ototoxicity blocks sensory regeneration in the avian inner ear.2010 Mar 3; 30 (9):3473-81. [PUBMED:20203207]
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[29]莫启忠,等.中医“肾”和耳联系的物质基础探讨-3H-醛固酮在豚鼠耳蜗和其它组织中的分布.中医杂志,1982；23(7)：69-71.
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[31]孙爱华,萧轼之,李兆基.从缺铁性肾虚大鼠耳蜗显微结构与生理功能变化探讨肾与耳联系的物质基础.中医研究.1993；6(3)：14-17.
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[36]Vilayur E,Gopinath B,Harris DC. The association between reduced GFR and hearing loss:a cross-sectional population based study. Am J Kidney Dis.2010; 56 (4):661-669.
[37]肖娟,罗志强.肾脏疾病与耳聋相关性.国际耳鼻咽喉头颈外科杂志.2007；31(6)：351-353.
[38]Anan H. Abbasi MD, Rawi Ramadan MD, Aaron Hoffman MD and Zaid Abassi PhD. Kidney-Ear Axis. IMAJ.2007; 9:814-818。
[39]Bielesz B, Sirin YHS, Niranjan T, et al. Epithelial notch signaling regulates interstitial fibrosis development in kidneys of mice and man. J Clin Invest.2010 Nov 1; 120(11):4040-54.
[40]Kavian N, Servettaz A, et al. Targeting ADAM-17/Notch signaling abrogates the development of systemic sclerosis in a murine model. ARTHRITIS.2010; 11 (62):3477-3487.
[41]魏敏,陆晓媛,缪璐.Y-分泌酶抑制剂.DAPT对人宫颈癌Hela细胞体外增殖的影响[J].辽宁医学院学报.2010,10(5)：390-392.
[42]Yan Hao, Jiang Fengchao. Recent Advances in the Research of γ-Secretase Inhibitors. PROGRESS IN CHEMISTRY.2006,3 (18):355-362.
[43]Chyung JH, Raper DM, Selkoe DJ. γ-Secretase exists on the plasma membrane as an intact complex that accepts substrates and effects intramembrane cleavage [J]. The Journal of Biological Chemistry,2005,280:4383.
[44]Takebayashi S, Yamamoto N, Yabe D, et al.Multile roles of Notch signaling in clchlear development[J]. Dev Biol, 2007,307:165.
[45]Yamamoto N, Tanigaki K, Tsuji M, et al. Inhibition of Notch/RBP-J signaling induced hair cell formation in neonate mouse cochleas [J]. J Mol Med,2006,84:37.
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