PMID- 37016580
OWN - NLM
STAT- MEDLINE
DCOM- 20230510
LR  - 20240504
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 31
IP  - 5
DP  - 2023 May 3
TI  - Epsin1-mediated exosomal sorting of Dll4 modulates the tubular-macrophage 
      crosstalk in diabetic nephropathy.
PG  - 1451-1467
LID - S1525-0016(23)00160-0 [pii]
LID - 10.1016/j.ymthe.2023.03.027 [doi]
AB  - Tubular epithelial cells (TECs) play critical roles in the development of 
      diabetic nephropathy (DN), and can activate macrophages through the secretion of 
      exosomes. However, the mechanism(s) of TEC-exosomes in macrophage activation 
      under DN remains unknown. By mass spectrometry, 1,644 differentially expressed 
      proteins, especially Dll4, were detected in the urine exosomes of DN patients 
      compared with controls, which was confirmed by western blot assay. Elevated 
      Epsin1 and Dll4/N1ICD expression was observed in kidney tissues in both DN 
      patients and db/db mice and was positively associated with tubulointerstitial 
      damage. Exosomes from high glucose (HG)-treated tubular cells (HK-2) with Epsin1 
      knockdown (KD) ameliorated macrophage activation, TNF-alpha, and IL-6 expression, and 
      tubulointerstitial damage in C57BL/6 mice in vivo. In an in vitro study, enriched 
      Dll4 was confirmed in HK-2 cells stimulated with HG, which was captured by THP-1 
      cells and promoted M1 macrophage activation. In addition, Epsin1 modulated the 
      content of Dll4 in TEC-exosomes stimulated with HG. TEC-exosomes with Epsin1-KD 
      significantly inhibited N1ICD activation and iNOS expression in THP-1 cells 
      compared with incubation with HG alone. These findings suggested that Epsin1 
      could modulate tubular-macrophage crosstalk in DN by mediating exosomal sorting 
      of Dll4 and Notch1 activation.
CI  - Copyright (c) 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
FAU - Liu, Jia-Lu
AU  - Liu JL
AD  - Department of Nephrology, The Second Xiangya Hospital, Central South University, 
      Changsha, Hunan, China.
FAU - Zhang, Lei
AU  - Zhang L
AD  - Department of Nephrology, The Second Xiangya Hospital, Central South University, 
      Changsha, Hunan, China.
FAU - Huang, Ying
AU  - Huang Y
AD  - Department of Nephrology, The Second Xiangya Hospital, Central South University, 
      Changsha, Hunan, China.
FAU - Li, Xiao-Hui
AU  - Li XH
AD  - Department of Nephrology, The Second Xiangya Hospital, Central South University, 
      Changsha, Hunan, China.
FAU - Liu, Yi-Fei
AU  - Liu YF
AD  - Department of Nephrology, The Second Xiangya Hospital, Central South University, 
      Changsha, Hunan, China.
FAU - Zhang, Shu-Min
AU  - Zhang SM
AD  - Department of Nephrology, The Second Xiangya Hospital, Central South University, 
      Changsha, Hunan, China.
FAU - Zhao, Yue-E
AU  - Zhao YE
AD  - Department of Nephrology, The Second Xiangya Hospital, Central South University, 
      Changsha, Hunan, China.
FAU - Chen, Xiao-Jun
AU  - Chen XJ
AD  - Department of Nephrology, The Second Xiangya Hospital, Central South University, 
      Changsha, Hunan, China.
FAU - Liu, Yu
AU  - Liu Y
AD  - Department of Nephrology, The Second Xiangya Hospital, Central South University, 
      Changsha, Hunan, China.
FAU - He, Li-Yu
AU  - He LY
AD  - Department of Nephrology, The Second Xiangya Hospital, Central South University, 
      Changsha, Hunan, China.
FAU - Dong, Zheng
AU  - Dong Z
AD  - Department of Nephrology, The Second Xiangya Hospital, Central South University, 
      Changsha, Hunan, China; Department of Cellular Biology and Anatomy, Medical 
      College of Georgia at Augusta University, Augusta, GA, USA; Charlie Norwood VA 
      Medical Center, Augusta, GA, USA.
FAU - Liu, Fu-You
AU  - Liu FY
AD  - Department of Nephrology, The Second Xiangya Hospital, Central South University, 
      Changsha, Hunan, China.
FAU - Sun, Lin
AU  - Sun L
AD  - Department of Nephrology, The Second Xiangya Hospital, Central South University, 
      Changsha, Hunan, China.
FAU - Xiao, Li
AU  - Xiao L
AD  - Department of Nephrology, The Second Xiangya Hospital, Central South University, 
      Changsha, Hunan, China. Electronic address: xiaolizndx@csu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230403
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - IY9XDZ35W2 (Glucose)
RN  - 0 (epsin)
RN  - 0 (DLL4 protein, mouse)
SB  - IM
MH  - Animals
MH  - Mice
MH  - Cell Movement
MH  - *Diabetes Mellitus/metabolism
MH  - *Diabetic Nephropathies/metabolism
MH  - Epithelial Cells/metabolism
MH  - Glucose/metabolism
MH  - Macrophages/metabolism
MH  - Mice, Inbred C57BL
PMC - PMC10188907
OTO - NOTNLM
OT  - Dll4
OT  - Epsin1
OT  - diabetic nephropathy
OT  - exosome
OT  - inflammation
COIS- Declaration of interests The authors declare no competing interests.
EDAT- 2023/04/06 06:00
MHDA- 2023/05/08 06:41
PMCR- 2024/05/03
CRDT- 2023/04/05 01:36
PHST- 2022/09/27 00:00 [received]
PHST- 2023/02/18 00:00 [revised]
PHST- 2023/03/28 00:00 [accepted]
PHST- 2023/05/08 06:41 [medline]
PHST- 2023/04/06 06:00 [pubmed]
PHST- 2023/04/05 01:36 [entrez]
PHST- 2024/05/03 00:00 [pmc-release]
AID - S1525-0016(23)00160-0 [pii]
AID - 10.1016/j.ymthe.2023.03.027 [doi]
PST - ppublish
SO  - Mol Ther. 2023 May 3;31(5):1451-1467. doi: 10.1016/j.ymthe.2023.03.027. Epub 2023 
      Apr 3.