Transfer of hepatocellular microRNA regulates cytochrome P450 2E1 in renal tubular cells.
Acute liver injury
Kidney function
Paracetamol
Signalling
microRNA
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Dec 2020
Dec 2020
Historique:
received:
07
08
2020
revised:
07
10
2020
accepted:
09
10
2020
pubmed:
25
11
2020
medline:
25
8
2021
entrez:
24
11
2020
Statut:
ppublish
Résumé
Extracellular microRNAs enter kidney cells and modify gene expression. We used a Dicer-hepatocyte-specific microRNA conditional-knock-out (Dicer-CKO) mouse to investigate microRNA transfer from liver to kidney. Dicer Dicer-CKO mice demonstrated a decrease in kidney miR-122 in the absence of other microRNA changes. During hepatotoxicity, miR-122 increased in kidney tubular cells; this was abolished in Dicer-CKO mice. Depletion of hepatocyte microRNA increased kidney cytochrome P450 2E1 expression and activity. Serum ECVs from mice with hepatotoxicity increased proximal tubular cell miR-122 and prevented cisplatin toxicity. miR-122 increased in urinary ECVs during human hepatotoxicity. Transfer of microRNA was not restricted to liver injury -miR-499 was released following cardiac injury and correlated with an increase in the kidney. Physiological transfer of functional microRNA to the kidney is increased by liver injury and this signalling represents a new paradigm for understanding the relationship between liver injury and renal function. Kidney Research UK, Medical Research Scotland, Medical Research Council.
Sections du résumé
BACKGROUND
BACKGROUND
Extracellular microRNAs enter kidney cells and modify gene expression. We used a Dicer-hepatocyte-specific microRNA conditional-knock-out (Dicer-CKO) mouse to investigate microRNA transfer from liver to kidney.
METHODS
METHODS
Dicer
FINDINGS
RESULTS
Dicer-CKO mice demonstrated a decrease in kidney miR-122 in the absence of other microRNA changes. During hepatotoxicity, miR-122 increased in kidney tubular cells; this was abolished in Dicer-CKO mice. Depletion of hepatocyte microRNA increased kidney cytochrome P450 2E1 expression and activity. Serum ECVs from mice with hepatotoxicity increased proximal tubular cell miR-122 and prevented cisplatin toxicity. miR-122 increased in urinary ECVs during human hepatotoxicity. Transfer of microRNA was not restricted to liver injury -miR-499 was released following cardiac injury and correlated with an increase in the kidney.
INTERPRETATION
CONCLUSIONS
Physiological transfer of functional microRNA to the kidney is increased by liver injury and this signalling represents a new paradigm for understanding the relationship between liver injury and renal function.
FUNDING
BACKGROUND
Kidney Research UK, Medical Research Scotland, Medical Research Council.
Identifiants
pubmed: 33232872
pii: S2352-3964(20)30468-0
doi: 10.1016/j.ebiom.2020.103092
pmc: PMC7689533
pii:
doi:
Substances chimiques
MicroRNAs
0
Mirn122 microRNA, mouse
0
Cytochrome P-450 CYP2E1
EC 1.14.13.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
103092Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest Author JWD is a member of the expert advisory group for the EU IMI funded TransBioLine Consortium. Author LD supervises a PhD studentship co-funded by Regulus Therapeutics and GSK.