• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

C3a受体拮抗剂通过抑制TGF-β/smad3和IKBα信号通路的激活，改善2型糖尿病肾病中的炎症和纤维化信号。

C3a receptor antagonist ameliorates inflammatory and fibrotic signals in type 2 diabetic nephropathy by suppressing the activation of TGF-β/smad3 and IKBα pathway.

作者信息

Li Ling, Yin Qinghua, Tang Xi, Bai Lin, Zhang Jie, Gou Shenju, Zhu Hongping, Cheng Jingqiu, Fu Ping, Liu Fang

机构信息

Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.

Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Regenerative Medicine Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China.

出版信息

PLoS One. 2014 Nov 25;9(11):e113639. doi: 10.1371/journal.pone.0113639. eCollection 2014.

DOI:10.1371/journal.pone.0113639
PMID:25422985
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4244104/
Abstract

OBJECTIVE

Diabetic nephropathy (DN) is a serious complication for patients with diabetes mellitus (DM). Emerging evidence suggests that complement C3a is involved in the progression of DN. The aim of this study was to investigate the effect of C3a Receptor Agonist (C3aRA) on DN and its potential mechanism of action in rats with type 2 diabetes mellitus (T2DM).

METHODS

T2DM was induced in SD rats by a high fat diet (HFD) plus repeated low dose streptozocin (STZ) injections. T2DM rats were treated with vehicle or C3aRA for 8 weeks. Biochemical analysis, HE and PAS stains were performed to evaluate the renal function and pathological changes. Human renal glomerular endothelial cells (HRGECs) were cultured and treated with normal glucose (NG), high glucose (HG), HG+C3a, HG+C3a+C3aRA and HG+C3a+BAY-11-7082 (p-IKBα Inhibitor) or SIS3 (Smad3 Inhibitor), respectively. Real-time PCR, immunofluorescent staining and western blot were performed to detect the mRNA and protein levels, respectively.

RESULTS

T2DM rats showed worse renal morphology and impaired renal function compared with control rats, including elevated levels of serum creatinine (CREA), blood urea nitrogen (BUN) and urine albumin excretion (UACR), as well as increased levels of C3a, C3aR, IL-6, p-IKBα, collagen I, TGF-β and p-Smad3 in the kidney of T2DM rats and C3a-treated HRGECs. In contrast, C3aRA treatment improved renal function and morphology, reduced CREA, UACR and the intensity of PAS and collagen I staining in the kidney of T2DM rats, and decreased C3a, p-IKBα, IL-6, TGF-β, p-Smad3 and collagen I expressions in HRGECs and T2DM rats.

CONCLUSION

C3a mediated pro-inflammatory and pro-fibrotic responses and aggravated renal injury in T2DM rats. C3aRA ameliorated T2DN by inhibiting IKBα phosphorylation and cytokine release, and also TGF-β/Smad3 signaling and ECM deposition. Therefore, complement C3a receptor is a potential therapeutic target for DN.

摘要

目的

糖尿病肾病（DN）是糖尿病（DM）患者的一种严重并发症。新出现的证据表明，补体C3a参与了DN的进展。本研究的目的是探讨C3a受体激动剂（C3aRA）对2型糖尿病（T2DM）大鼠DN的影响及其潜在作用机制。

方法

通过高脂饮食（HFD）加重复低剂量链脲佐菌素（STZ）注射诱导SD大鼠发生T2DM。T2DM大鼠用溶剂或C3aRA治疗8周。进行生化分析、HE和PAS染色以评估肾功能和病理变化。培养人肾小球内皮细胞（HRGECs），并分别用正常葡萄糖（NG）、高糖（HG）、HG+C3a、HG+C3a+C3aRA和HG+C3a+BAY-11-7082（p-IκBα抑制剂）或SIS3（Smad3抑制剂）处理。分别进行实时PCR、免疫荧光染色和western印迹以检测mRNA和蛋白水平。

结果

与对照大鼠相比，T2DM大鼠表现出更差的肾脏形态和受损的肾功能，包括血清肌酐（CREA）、血尿素氮（BUN）和尿白蛋白排泄（UACR）水平升高，以及T2DM大鼠肾脏和C3a处理的HRGECs中C3a、C3aR、IL-6、p-IκBα、I型胶原、TGF-β和p-Smad3水平升高。相反，C3aRA治疗改善了肾功能和形态，降低了T2DM大鼠肾脏中的CREA、UACR以及PAS和I型胶原染色强度，并降低了HRGECs和T2DM大鼠中C3a、p-IκBα、IL-6、TGF-β、p-Smad3和I型胶原的表达。

结论

C3a介导了T2DM大鼠的促炎和促纤维化反应并加重了肾损伤。C3aRA通过抑制IκBα磷酸化和细胞因子释放，以及TGF-β/Smad3信号传导和细胞外基质沉积来改善T2DN。因此，补体C3a受体是DN的一个潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e7c/4244104/7b09e5ae8873/pone.0113639.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e7c/4244104/775c2bebf491/pone.0113639.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e7c/4244104/fc02027bf32f/pone.0113639.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e7c/4244104/d58352c15c63/pone.0113639.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e7c/4244104/2c2a43b358f4/pone.0113639.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e7c/4244104/a098f994c974/pone.0113639.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e7c/4244104/497fa298498c/pone.0113639.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e7c/4244104/7b09e5ae8873/pone.0113639.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e7c/4244104/775c2bebf491/pone.0113639.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e7c/4244104/fc02027bf32f/pone.0113639.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e7c/4244104/d58352c15c63/pone.0113639.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e7c/4244104/2c2a43b358f4/pone.0113639.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e7c/4244104/a098f994c974/pone.0113639.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e7c/4244104/497fa298498c/pone.0113639.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e7c/4244104/7b09e5ae8873/pone.0113639.g007.jpg

相似文献

1
C3a receptor antagonist ameliorates inflammatory and fibrotic signals in type 2 diabetic nephropathy by suppressing the activation of TGF-β/smad3 and IKBα pathway.C3a受体拮抗剂通过抑制TGF-β/smad3和IKBα信号通路的激活，改善2型糖尿病肾病中的炎症和纤维化信号。
PLoS One. 2014 Nov 25;9(11):e113639. doi: 10.1371/journal.pone.0113639. eCollection 2014.
2
C3a and C5a receptor antagonists ameliorate endothelial-myofibroblast transition via the Wnt/β-catenin signaling pathway in diabetic kidney disease.C3a 和 C5a 受体拮抗剂通过 Wnt/β-连环蛋白信号通路改善糖尿病肾病中的内皮-肌成纤维细胞转化。
Metabolism. 2015 May;64(5):597-610. doi: 10.1016/j.metabol.2015.01.014. Epub 2015 Jan 29.
3
Roux-en-Y Esophagojejunostomy Ameliorates Renal Function Through Reduction of Renal Inflammatory and Fibrotic Markers in Diabetic Nephropathy.Roux-en-Y食管空肠吻合术通过降低糖尿病肾病患者的肾脏炎症和纤维化标志物来改善肾功能。
Obes Surg. 2016 Jul;26(7):1402-13. doi: 10.1007/s11695-015-1947-5.
4
Effects of Bone Marrow Mesenchymal Stem Cells on Plasminogen Activator Inhibitor-1 and Renal Fibrosis in Rats with Diabetic Nephropathy.骨髓间充质干细胞对糖尿病肾病大鼠纤溶酶原激活物抑制剂-1及肾纤维化的影响
Arch Med Res. 2016 Feb;47(2):71-7. doi: 10.1016/j.arcmed.2016.03.002. Epub 2016 Mar 24.
5
Betanin, isolated from fruits of Opuntia elatior Mill attenuates renal fibrosis in diabetic rats through regulating oxidative stress and TGF-β pathway.从刺梨果实中分离出的甜菜红素通过调节氧化应激和转化生长因子-β通路减轻糖尿病大鼠的肾纤维化。
J Ethnopharmacol. 2017 Feb 23;198:432-443. doi: 10.1016/j.jep.2016.12.048. Epub 2017 Jan 20.
6
[The effect of complement C3a receptor antagonist in the kidney immune injury in trichloroethylene-sensitized mice].[补体C3a受体拮抗剂对三氯乙烯致敏小鼠肾脏免疫损伤的影响]
Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2017 Mar 20;35(3):161-165. doi: 10.3760/cma.j.issn.1001-9391.2017.03.001.
7
Dencichine ameliorates kidney injury in induced type II diabetic nephropathy via the TGF-β/Smad signalling pathway.地昔昔定通过 TGF-β/Smad 信号通路改善诱导型 2 型糖尿病肾病的肾脏损伤。
Eur J Pharmacol. 2017 Oct 5;812:196-205. doi: 10.1016/j.ejphar.2017.06.024. Epub 2017 Jun 17.
8
C3a receptor blockade protects podocytes from injury in diabetic nephropathy.C3a 受体阻断可保护糖尿病肾病足细胞免受损伤。
JCI Insight. 2020 Mar 12;5(5):131849. doi: 10.1172/jci.insight.131849.
9
Effect of anaphylatoxin C3a, C5a on the tubular epithelial-myofibroblast transdifferentiation in vitro.过敏毒素 C3a、C5a 对体外肾小管上皮细胞-肌成纤维细胞转分化的影响。
Chin Med J (Engl). 2011 Dec;124(23):4039-45.
10
Combination of leflunomide and benazepril reduces renal injury of diabetic nephropathy rats and inhibits high-glucose induced cell apoptosis through regulation of NF-κB, TGF-β and TRPC6.来氟米特联合贝那普利减少糖尿病肾病大鼠肾损伤并通过调控 NF-κB、TGF-β和 TRPC6 抑制高糖诱导的细胞凋亡。
Ren Fail. 2019 Nov;41(1):899-906. doi: 10.1080/0886022X.2019.1665547.

引用本文的文献

1
C3AR1 may aggravate diabetic nephropathy by mediating oxidative stress via ITGB2 regulation in renal tubular epithelial cells.C3AR1可能通过在肾小管上皮细胞中经由ITGB2调控介导氧化应激来加重糖尿病肾病。
PLoS One. 2025 Sep 12;20(9):e0331900. doi: 10.1371/journal.pone.0331900. eCollection 2025.
2
Renal Epithelial Complement C3 Expression Affects Kidney Fibrosis Progression.肾上皮补体C3表达影响肾纤维化进展。
Int J Mol Sci. 2024 Nov 22;25(23):12551. doi: 10.3390/ijms252312551.
3
Complement anaphylatoxins: Potential therapeutic target for diabetic kidney disease.

本文引用的文献

1
Cell biology of diabetic nephropathy: Roles of endothelial cells, tubulointerstitial cells and podocytes.糖尿病肾病的细胞生物学：内皮细胞、肾小管间质细胞和足细胞的作用
J Diabetes Investig. 2015 Jan;6(1):3-15. doi: 10.1111/jdi.12255. Epub 2014 Jul 11.
2
Shiga toxin promotes podocyte injury in experimental hemolytic uremic syndrome via activation of the alternative pathway of complement.志贺毒素通过激活补体替代途径促进实验性溶血尿毒综合征中的足细胞损伤。
J Am Soc Nephrol. 2014 Aug;25(8):1786-98. doi: 10.1681/ASN.2013050450. Epub 2014 Feb 27.
3
1H NMR-based metabonomic analysis of serum and urine in a nonhuman primate model of diabetic nephropathy.
补体过敏毒素：糖尿病肾病的潜在治疗靶点。
Diabet Med. 2025 Feb;42(2):e15427. doi: 10.1111/dme.15427. Epub 2024 Aug 27.
4
Diabetic complications and prospective immunotherapy.糖尿病并发症与前瞻性免疫疗法。
Front Immunol. 2023 Jul 7;14:1219598. doi: 10.3389/fimmu.2023.1219598. eCollection 2023.
5
Integrative network-based analysis on multiple Gene Expression Omnibus datasets identifies novel immune molecular markers implicated in non-alcoholic steatohepatitis.基于整合网络的多个基因表达综合数据集分析鉴定了非酒精性脂肪性肝炎中涉及的新型免疫分子标志物。
Front Endocrinol (Lausanne). 2023 Mar 16;14:1115890. doi: 10.3389/fendo.2023.1115890. eCollection 2023.
6
Immune responses in diabetic nephropathy: Pathogenic mechanisms and therapeutic target.糖尿病肾病中的免疫反应：发病机制和治疗靶点。
Front Immunol. 2022 Aug 15;13:958790. doi: 10.3389/fimmu.2022.958790. eCollection 2022.
7
C3c deposition predicts worse renal outcomes in patients with biopsy-proven diabetic kidney disease in type 2 diabetes mellitus.C3c 沉积可预测 2 型糖尿病患者经活检证实的糖尿病肾病的肾脏不良结局。
J Diabetes. 2022 Apr;14(4):291-297. doi: 10.1111/1753-0407.13264. Epub 2022 Mar 24.
8
Cellular crosstalk of glomerular endothelial cells and podocytes in diabetic kidney disease.糖尿病肾病中肾小球内皮细胞与足细胞的细胞间相互作用
J Cell Commun Signal. 2022 Sep;16(3):313-331. doi: 10.1007/s12079-021-00664-w. Epub 2022 Jan 18.
9
Renal diseases and the role of complement: Linking complement to immune effector pathways and therapeutics.肾脏疾病与补体的作用：将补体与免疫效应途径和治疗联系起来。
Adv Immunol. 2021;152:1-81. doi: 10.1016/bs.ai.2021.09.001. Epub 2021 Nov 19.
10
The Complement Pathway: New Insights into Immunometabolic Signaling in Diabetic Kidney Disease.补体途径：糖尿病肾病中免疫代谢信号的新见解。
Antioxid Redox Signal. 2022 Oct;37(10-12):781-801. doi: 10.1089/ars.2021.0125. Epub 2022 Feb 7.
基于1H核磁共振的糖尿病肾病非人灵长类动物模型血清和尿液代谢组学分析
Mol Biosyst. 2013 Nov;9(11):2645-52. doi: 10.1039/c3mb70212j.
4
Complement in immune and inflammatory disorders: pathophysiological mechanisms.补体在免疫和炎症性疾病中的作用：病理生理机制。
J Immunol. 2013 Apr 15;190(8):3831-8. doi: 10.4049/jimmunol.1203487.
5
Mechanisms of diabetic complications.糖尿病并发症的发病机制。
Physiol Rev. 2013 Jan;93(1):137-88. doi: 10.1152/physrev.00045.2011.
6
The glomerular endothelium emerges as a key player in diabetic nephropathy.肾小球内皮细胞在糖尿病肾病中表现为关键角色。
Kidney Int. 2012 Nov;82(9):949-51. doi: 10.1038/ki.2012.258.
7
Effect of anaphylatoxin C3a, C5a on the tubular epithelial-myofibroblast transdifferentiation in vitro.过敏毒素 C3a、C5a 对体外肾小管上皮细胞-肌成纤维细胞转分化的影响。
Chin Med J (Engl). 2011 Dec;124(23):4039-45.
8
Diagnosis and classification of diabetes mellitus.糖尿病的诊断与分类
Diabetes Care. 2012 Jan;35 Suppl 1(Suppl 1):S64-71. doi: 10.2337/dc12-s064.
9
Diverse roles of TGF-β/Smads in renal fibrosis and inflammation.TGF-β/Smads 在肾脏纤维化和炎症中的多种作用。
Int J Biol Sci. 2011;7(7):1056-67. doi: 10.7150/ijbs.7.1056. Epub 2011 Sep 2.
10
Distinct roles for C3a and C5a in complement-induced tubulointerstitial injury.C3a 和 C5a 在补体诱导的肾小管间质损伤中具有不同的作用。
Kidney Int. 2011 Sep;80(5):524-34. doi: 10.1038/ki.2011.158. Epub 2011 Jun 15.