Titre
Impaired fatty acid metabolism perpetuates lipotoxicity along the transition to chronic kidney injury.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Rinaldi, A.
Auteure/Auteur
Lazareth, H.
Auteure/Auteur
Poindessous, V.
Auteure/Auteur
Nemazanyy, I.
Auteure/Auteur
Sampaio, J.L.
Auteure/Auteur
Malpetti, D.
Auteure/Auteur
Bignon, Y.
Auteure/Auteur
Naesens, M.
Auteure/Auteur
Rabant, M.
Auteure/Auteur
Anglicheau, D.
Auteure/Auteur
Cippà, P.E.
Auteure/Auteur
Pallet, N.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
2379-3708
Statut éditorial
Publié
Date de publication
2022-09-22
Volume
7
Numéro
18
Première page
e161783
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Publication Status: epublish
Résumé
Energy metabolism failure in proximal tubule cells (PTCs) is a hallmark of chronic kidney injury. We combined transcriptomic, metabolomic, and lipidomic approaches in experimental models and patient cohorts to investigate the molecular basis of the progression to chronic kidney allograft injury initiated by ischemia/reperfusion injury (IRI). The urinary metabolome of kidney transplant recipients with chronic allograft injury and who experienced severe IRI was substantially enriched with long chain fatty acids (FAs). We identified a renal FA-related gene signature with low levels of carnitine palmitoyltransferase 2 (Cpt2) and acyl-CoA synthetase medium chain family member 5 (Acsm5) and high levels of acyl-CoA synthetase long chain family member 4 and 5 (Acsl4 and Acsl5) associated with IRI, transition to chronic injury, and established chronic kidney disease in mouse models and kidney transplant recipients. The findings were consistent with the presence of Cpt2-Acsl4+Acsl5+Acsm5- PTCs failing to recover from IRI as identified by single-nucleus RNA-Seq. In vitro experiments indicated that ER stress contributed to CPT2 repression, which, in turn, promoted lipids' accumulation, drove profibrogenic epithelial phenotypic changes, and activated the unfolded protein response. ER stress through CPT2 inhibition and lipid accumulation engaged an auto-amplification loop leading to lipotoxicity and self-sustained cellular stress. Thus, IRI imprints a persistent FA metabolism disturbance in the proximal tubule, sustaining the progression to chronic kidney allograft injury.
PID Serval
serval:BIB_0BCFCD113A11
PMID
Open Access
Oui
Date de création
2022-08-29T07:43:06.046Z
Date de création dans IRIS
2025-05-20T16:12:41Z
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Nom
35998043_BIB_0BCFCD113A11.pdf
Version du manuscrit
published
Licence
https://creativecommons.org/licenses/by/4.0
Taille
11.14 MB
Format
Adobe PDF
PID Serval
serval:BIB_0BCFCD113A11.P001
URN
urn:nbn:ch:serval-BIB_0BCFCD113A113
Somme de contrôle
(MD5):e887642ea1d69259a6246ca80f39fd8a