Four-jointed knock-out delays renal failure in an ADPKD model with kidney injury.
Acute Kidney Injury
/ chemically induced
Animals
Cysteine
/ analogs & derivatives
Disease Models, Animal
Disease Progression
Fibrosis
Inflammation Mediators
/ metabolism
Intercellular Signaling Peptides and Proteins
/ deficiency
Kidney
/ metabolism
Kidney Failure, Chronic
/ etiology
Male
Mice, Knockout
Mutation
Polycystic Kidney, Autosomal Dominant
/ complications
TRPP Cation Channels
/ genetics
Time Factors
Wnt Signaling Pathway
ADPKD
cell polarity
fibrosis
kidney injury
Journal
The Journal of pathology
ISSN: 1096-9896
Titre abrégé: J Pathol
Pays: England
ID NLM: 0204634
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
05
12
2018
revised:
19
04
2019
accepted:
26
04
2019
pubmed:
1
5
2019
medline:
14
4
2020
entrez:
1
5
2019
Statut:
ppublish
Résumé
Autosomal Dominant Polycystic Kidney Disease is characterised by the development of fluid-filled cysts in the kidneys which lead to end-stage renal disease (ESRD). In the majority of cases, the disease is caused by a mutation in the Pkd1 gene. In a previous study, we demonstrated that renal injury can accelerate cyst formation in Pkd1 knock-out (KO) mice. In that study, we found that after injury four-jointed (Fjx1), an upstream regulator of planar cell polarity and the Hippo pathway, was aberrantly expressed in Pkd1 KO mice compared to WT. Therefore, we hypothesised a role for Fjx1 in injury/repair and cyst formation. We generated single and double deletion mice for Pkd1 and Fjx1, and we induced toxic renal injury using the nephrotoxic compound 1,2-dichlorovinyl-cysteine. We confirmed that nephrotoxic injury can accelerate cyst formation in Pkd1 mutant mice. This caused Pkd1 KO mice to reach ESRD significantly faster; unexpectedly, double KO mice survived significantly longer. Cyst formation was comparable in both models, but we found significantly less fibrosis and macrophage infiltration in double KO mice. Taken together, these data suggest that Fjx1 disruption protects the cystic kidneys against kidney failure by reducing inflammation and fibrosis. Moreover, we describe, for the first time, an interesting (yet unidentified) mechanism that partially discriminates cyst growth from fibrogenesis. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Identifiants
pubmed: 31038742
doi: 10.1002/path.5286
pmc: PMC6772084
doi:
Substances chimiques
Fjx1 protein, mouse
0
Inflammation Mediators
0
Intercellular Signaling Peptides and Proteins
0
TRPP Cation Channels
0
polycystic kidney disease 1 protein
0
S-(1,2-dichlorovinyl)cysteine
627-72-5
Cysteine
K848JZ4886
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
114-125Informations de copyright
© 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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