Endothelin converting enzyme-1 (ECE-1) deletion in association with Endothelin-1 downregulation ameliorates kidney fibrosis in mice.
Endothelin converting enzyme-1 (ECE-1)
Endothelin-1
Fibroblast
Inflammation
Kidney fibrosis
Myofibroblast
Journal
Life sciences
ISSN: 1879-0631
Titre abrégé: Life Sci
Pays: Netherlands
ID NLM: 0375521
Informations de publication
Date de publication:
01 Oct 2020
01 Oct 2020
Historique:
received:
16
04
2020
revised:
01
08
2020
accepted:
03
08
2020
pubmed:
10
8
2020
medline:
2
10
2020
entrez:
10
8
2020
Statut:
ppublish
Résumé
Kidney fibrosis is a common final pathway of chronic kidney diseases, which are characterized by renal architecture damage, inflammation, fibroblast expansion and myofibroblast formation. Endothelin converting enzyme-1 (ECE-1) contributes to activation of Endothelin-1 (ET-1), a potent vasoconstrictor and pro-fibrotic substance. This study elucidated the effect of ECE-1 knockout in kidney fibrosis model in mice in association of ET-1 downregulation. Kidney fibrosis was performed in ECE-1 knockout (ECE-1 KO) and vascular endothelial derived ET-1 KO (VEETKO) mice (2 months, 20-30 g, n = 30) and their wild type (WT) littermates using unilateral ureteral obstruction (UUO) procedure. Mice were euthanized on day-7 and day-14 after UUO. Histopathological analysis was conducted for fibrosis and tubular injury. Immunostainings were done to quantify macrophages (F4/80), fibroblasts (FSP-1) and myofibroblasts (α-SMA). Monocyte Chemoattractant Protein-1 (MCP-1), ECE-1 and preproET-1 (ppET-1) mRNA expression were quantified with qRT-PCR, while Transforming Growth Factor-β1 (TGF-β1) and α-SMA protein level were quantified with Western blot. ECE-1 KO mice demonstrated reduction of ECE-1 and ppET-1 mRNA expression, attenuation of kidney fibrosis, tubular injury, MCP-1 mRNA expression and macrophage number compared to WT. Double immunostaining revealed fibroblast to myofibroblast formation after UUO, while ECE-1 KO mice had significantly lower fibroblast number and myofibroblast formation compared to WT, which were associated with significantly lower TGF-β1 and α-SMA protein levels in day-14 of UUO. VEETKO mice also demonstrated attenuation of ET-1 protein level, fibrosis and myofibroblast formation. In conclusion, ECE-1 knockout and ET-1 downregulation attenuated kidney fibrosis.
Identifiants
pubmed: 32768584
pii: S0024-3205(20)30975-9
doi: 10.1016/j.lfs.2020.118223
pii:
doi:
Substances chimiques
Endothelin-1
0
Ece1 protein, mouse
EC 3.4.24.71
Endothelin-Converting Enzymes
EC 3.4.24.71
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
118223Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare that there are no conflicts of interest.