• 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

天冬酰胺内肽酶通过裂解原肌球蛋白-1来保护糖尿病肾病中的足细胞免受损伤。

Asparaginyl endopeptidase protects against podocyte injury in diabetic nephropathy through cleaving cofilin-1.

机构信息

Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.

出版信息

Cell Death Dis. 2022 Feb 25;13(2):184. doi: 10.1038/s41419-022-04621-2.

DOI:10.1038/s41419-022-04621-2
PMID:35217650
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8881581/
Abstract

Podocyte injury and loss are critical events in diabetic nephropathy (DN); however, the underlying molecular mechanisms remain unclear. Here, we demonstrate that asparaginyl endopeptidase (AEP) protects against podocyte injury through modulating the dynamics of the cytoskeleton. AEP was highly upregulated in diabetic glomeruli and hyperglycemic stimuli treated-podocytes; however, AEP gene knockout and its compound inhibitor treatment accelerated DN in streptozotocin-induced diabetic mice, whereas specific induction of AEP in glomerular cells attenuated podocyte injury and renal function deterioration. In vitro, elevated AEP was involved in actin cytoskeleton maintenance and anti-apoptosis effects. Mechanistically, we found that AEP directly cleaved the actin-binding protein cofilin-1 after the asparagine 138 (N138) site. The protein levels of endogenous cofilin-1 1-138 fragments were upregulated in diabetic podocytes, consistent with the changes in AEP levels. Importantly, we found that cofilin-1 1-138 fragments were remarkably unphosphorylated than full-length cofilin-1, indicating the enhanced cytoskeleton maintenance activity of cofilin-1 1-138. Then we validated cofilin-1 1-138 could rescue podocytes from cytoskeleton disarrangement and injury in diabetic conditions. Taken together, our data suggest a protective role of elevated AEP in podocyte injury during DN progression through cleaving cofilin-1 to maintain podocyte cytoskeleton dynamics and defend damage.

摘要

足细胞损伤和丢失是糖尿病肾病 (DN) 的关键事件；然而，其潜在的分子机制尚不清楚。在这里，我们证明天冬酰胺内肽酶 (AEP) 通过调节细胞骨架的动态来保护足细胞免受损伤。AEP 在糖尿病肾小球和高糖刺激处理的足细胞中高度上调；然而，AEP 基因敲除及其化合物抑制剂治疗加速了链脲佐菌素诱导的糖尿病小鼠的 DN，而在肾小球细胞中特异性诱导 AEP 则减轻了足细胞损伤和肾功能恶化。在体外，升高的 AEP 参与肌动蛋白细胞骨架的维持和抗细胞凋亡作用。在机制上，我们发现 AEP 在天冬酰胺 138 (N138) 位点后直接切割肌动蛋白结合蛋白原肌球蛋白 1。糖尿病足细胞中内源性原肌球蛋白 1 1-138 片段的蛋白水平上调，与 AEP 水平的变化一致。重要的是，我们发现原肌球蛋白 1 1-138 片段的磷酸化程度明显低于全长原肌球蛋白 1，表明原肌球蛋白 1 1-138 的细胞骨架维持活性增强。然后，我们验证了原肌球蛋白 1 1-138 可以在糖尿病条件下拯救足细胞免受细胞骨架紊乱和损伤。总之，我们的数据表明，在 DN 进展过程中，升高的 AEP 通过切割原肌球蛋白 1 来维持足细胞细胞骨架动力学和抵御损伤，从而在足细胞损伤中发挥保护作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43ed/8881581/af8505ab4027/41419_2022_4621_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43ed/8881581/ee765ab24126/41419_2022_4621_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43ed/8881581/d4c5e6254bfc/41419_2022_4621_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43ed/8881581/0fb2e2966887/41419_2022_4621_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43ed/8881581/51dce878387a/41419_2022_4621_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43ed/8881581/1e0530be1ca0/41419_2022_4621_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43ed/8881581/90137d18269f/41419_2022_4621_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43ed/8881581/4241379b236e/41419_2022_4621_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43ed/8881581/af8505ab4027/41419_2022_4621_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43ed/8881581/ee765ab24126/41419_2022_4621_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43ed/8881581/d4c5e6254bfc/41419_2022_4621_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43ed/8881581/0fb2e2966887/41419_2022_4621_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43ed/8881581/51dce878387a/41419_2022_4621_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43ed/8881581/1e0530be1ca0/41419_2022_4621_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43ed/8881581/90137d18269f/41419_2022_4621_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43ed/8881581/4241379b236e/41419_2022_4621_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43ed/8881581/af8505ab4027/41419_2022_4621_Fig8_HTML.jpg

相似文献

1
Asparaginyl endopeptidase protects against podocyte injury in diabetic nephropathy through cleaving cofilin-1.天冬酰胺内肽酶通过裂解原肌球蛋白-1来保护糖尿病肾病中的足细胞免受损伤。
Cell Death Dis. 2022 Feb 25;13(2):184. doi: 10.1038/s41419-022-04621-2.
2
Asparagine endopeptidase protects podocytes in adriamycin-induced nephropathy by regulating actin dynamics through cleaving transgelin.天冬酰胺内肽酶通过裂解转谷氨酰胺酶调控肌动蛋白动力学来保护阿霉素肾病足细胞。
Mol Ther. 2023 Nov 1;31(11):3337-3354. doi: 10.1016/j.ymthe.2023.09.003. Epub 2023 Sep 9.
3
Protein S Protects against Podocyte Injury in Diabetic Nephropathy.蛋白 S 可预防糖尿病肾病中的足细胞损伤。
J Am Soc Nephrol. 2018 May;29(5):1397-1410. doi: 10.1681/ASN.2017030234. Epub 2018 Mar 6.
4
Podocyte RNF166 deficiency alleviates diabetic nephropathy by mitigating mitochondria impairment and apoptosis via regulation of CYLD signal.足细胞 RNF166 缺乏通过调节 CYLD 信号减轻糖尿病肾病的线粒体损伤和凋亡。
Biochem Biophys Res Commun. 2021 Mar 19;545:46-53. doi: 10.1016/j.bbrc.2020.12.014. Epub 2021 Feb 2.
5
GPR43 deficiency protects against podocyte insulin resistance in diabetic nephropathy through the restoration of AMPKα activity.GPR43 缺乏通过恢复 AMPKα 活性来保护糖尿病肾病中的足细胞胰岛素抵抗。
Theranostics. 2021 Mar 4;11(10):4728-4742. doi: 10.7150/thno.56598. eCollection 2021.
6
MAD2B promotes podocyte injury through regulating Numb-dependent Notch 1 pathway in diabetic nephropathy.MAD2B 通过调节 Notch1 通路促进糖尿病肾病足细胞损伤。
Int J Biol Sci. 2022 Feb 21;18(5):1896-1911. doi: 10.7150/ijbs.68977. eCollection 2022.
7
Astragaloside IV protects against podocyte apoptosis by inhibiting oxidative stress via activating PPARγ-Klotho-FoxO1 axis in diabetic nephropathy.黄芪甲苷通过激活 PPARγ-Klotho-FoxO1 轴抑制氧化应激来保护糖尿病肾病中的足细胞凋亡。
Life Sci. 2021 Mar 15;269:119068. doi: 10.1016/j.lfs.2021.119068. Epub 2021 Jan 18.
8
Inhibition of NLRP3 inflammasome ameliorates podocyte damage by suppressing lipid accumulation in diabetic nephropathy.NLRP3 炎性小体抑制可通过抑制脂滴蓄积改善糖尿病肾病足细胞损伤。
Metabolism. 2021 May;118:154748. doi: 10.1016/j.metabol.2021.154748. Epub 2021 Mar 4.
9
RhoA protects the podocytes against high glucose-induced apoptosis through YAP and plays critical role in diabetic nephropathy.RhoA 通过 YAP 保护足细胞免受高糖诱导的细胞凋亡，在糖尿病肾病中发挥关键作用。
Biochem Biophys Res Commun. 2018 Oct 12;504(4):949-956. doi: 10.1016/j.bbrc.2018.08.204. Epub 2018 Sep 14.
10
Ezrin is down-regulated in diabetic kidney glomeruli and regulates actin reorganization and glucose uptake via GLUT1 in cultured podocytes.Ezrin 在糖尿病肾病肾小球中下调，并通过培养的足细胞中的 GLUT1 调节肌动蛋白重组和葡萄糖摄取。
Am J Pathol. 2014 Jun;184(6):1727-39. doi: 10.1016/j.ajpath.2014.03.002. Epub 2014 Apr 13.

引用本文的文献

1
DOT1L protects against podocyte injury in diabetic kidney disease through phospholipase C-like 1.DOT1L 通过类磷酯酶 C 样蛋白 1 保护糖尿病肾病中的足细胞免受损伤。
Cell Commun Signal. 2024 Oct 25;22(1):519. doi: 10.1186/s12964-024-01895-1.
2
Correlation analysis of cofilin-1 with renal prognosis in primary IgA nephropathy.伴肌动蛋白-1 与原发性 IgA 肾病肾预后的相关性分析。
BMC Nephrol. 2024 Sep 3;25(1):289. doi: 10.1186/s12882-024-03723-7.
3
Common proteins analysis of different mammals' mature milk by 4D-Label-Free.利用4D无标记技术对不同哺乳动物成熟乳进行常见蛋白质分析。

本文引用的文献

1
New insight into podocyte slit diaphragm, a therapeutic target of proteinuria.对足细胞裂孔隔膜的新认识，蛋白尿的治疗靶点。
Clin Exp Nephrol. 2020 Mar;24(3):193-204. doi: 10.1007/s10157-020-01854-3. Epub 2020 Feb 4.
2
US Renal Data System 2019 Annual Data Report: Epidemiology of Kidney Disease in the United States.美国肾脏数据系统2019年年报：美国肾脏疾病流行病学
Am J Kidney Dis. 2020 Jan;75(1 Suppl 1):A6-A7. doi: 10.1053/j.ajkd.2019.09.003. Epub 2019 Nov 5.
3
Mammalian legumain - A lysosomal cysteine protease with extracellular functions?
Food Chem X. 2024 Mar 1;22:101263. doi: 10.1016/j.fochx.2024.101263. eCollection 2024 Jun 30.
4
Cytoskeleton Rearrangement in Podocytopathies: An Update.足细胞病中细胞骨架重排：最新研究进展。
Int J Mol Sci. 2024 Jan 4;25(1):647. doi: 10.3390/ijms25010647.
5
Urinary exosome proteins PAK6 and EGFR as noninvasive diagnostic biomarkers of diabetic nephropathy.尿外泌体蛋白 PAK6 和 EGFR 作为糖尿病肾病的无创诊断生物标志物。
BMC Nephrol. 2023 Oct 3;24(1):291. doi: 10.1186/s12882-023-03343-7.
6
Asparagine endopeptidase protects podocytes in adriamycin-induced nephropathy by regulating actin dynamics through cleaving transgelin.天冬酰胺内肽酶通过裂解转谷氨酰胺酶调控肌动蛋白动力学来保护阿霉素肾病足细胞。
Mol Ther. 2023 Nov 1;31(11):3337-3354. doi: 10.1016/j.ymthe.2023.09.003. Epub 2023 Sep 9.
7
Bibliometric Analysis and Visualization of Research Progress in the Diabetic Nephropathy Field from 2001 to 2021.2001 年至 2021 年糖尿病肾病领域研究进展的文献计量学分析与可视化
Oxid Med Cell Longev. 2023 Jan 21;2023:4555609. doi: 10.1155/2023/4555609. eCollection 2023.
8
The Mammalian Cysteine Protease Legumain in Health and Disease.哺乳动物半胱氨酸蛋白酶组织蛋白酶 L 在健康和疾病中的作用。
Int J Mol Sci. 2022 Dec 15;23(24):15983. doi: 10.3390/ijms232415983.
哺乳动物组织蛋白酶 L- 一种具有细胞外功能的溶酶体半胱氨酸蛋白酶？
Biochimie. 2019 Nov;166:77-83. doi: 10.1016/j.biochi.2019.06.002. Epub 2019 Jun 7.
4
Long noncoding RNA inhibits renal fibrogenesis by negatively regulating the TGF-β/Smad3 pathway.长链非编码 RNA 通过负调控 TGF-β/Smad3 通路抑制肾纤维化。
Sci Transl Med. 2018 Oct 10;10(462). doi: 10.1126/scitranslmed.aat2039.
5
Understanding Podocyte Biology to Develop Novel Kidney Therapeutics.了解足细胞生物学以开发新型肾脏治疗方法。
Front Endocrinol (Lausanne). 2018 Jul 23;9:409. doi: 10.3389/fendo.2018.00409. eCollection 2018.
6
Legumain, an asparaginyl endopeptidase, mediates the effect of M2 macrophages on attenuating renal interstitial fibrosis in obstructive nephropathy.组织蛋白酶 S，一种天冬酰胺内肽酶，介导 M2 巨噬细胞减轻梗阻性肾病肾间质纤维化的作用。
Kidney Int. 2018 Jul;94(1):91-101. doi: 10.1016/j.kint.2017.12.025. Epub 2018 Apr 12.
7
Update of pathophysiology and management of diabetic kidney disease.糖尿病肾病的病理生理学和治疗进展。
J Formos Med Assoc. 2018 Aug;117(8):662-675. doi: 10.1016/j.jfma.2018.02.007. Epub 2018 Mar 2.
8
The classic signalling and trans-signalling of interleukin-6 are both injurious in podocyte under high glucose exposure.在高糖环境下，白细胞介素-6 的经典信号转导和转信号转导对足细胞均具有损伤作用。
J Cell Mol Med. 2018 Jan;22(1):251-260. doi: 10.1111/jcmm.13314. Epub 2017 Sep 7.
9
MDM2 Contributes to High Glucose-Induced Glomerular Mesangial Cell Proliferation and Extracellular Matrix Accumulation via Notch1.MDM2 通过 Notch1 促进高糖诱导的肾小球系膜细胞增殖和细胞外基质积聚。
Sci Rep. 2017 Sep 4;7(1):10393. doi: 10.1038/s41598-017-10927-5.
10
Sirt6 deficiency exacerbates podocyte injury and proteinuria through targeting Notch signaling.沉默调节蛋白6缺陷通过靶向Notch信号通路加重足细胞损伤和蛋白尿。
Nat Commun. 2017 Sep 4;8(1):413. doi: 10.1038/s41467-017-00498-4.