Sirtuin 5 Regulates Proximal Tubule Fatty Acid Oxidation to Protect against AKI.
Fatty acid oxidation
Peroxisome
Post translational modifications
Sirtuins
acute kidney injury
mitochondria
Journal
Journal of the American Society of Nephrology : JASN
ISSN: 1533-3450
Titre abrégé: J Am Soc Nephrol
Pays: United States
ID NLM: 9013836
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
18
02
2019
accepted:
29
08
2019
pubmed:
3
10
2019
medline:
9
6
2020
entrez:
3
10
2019
Statut:
ppublish
Résumé
The primary site of damage during AKI, proximal tubular epithelial cells, are highly metabolically active, relying on fatty acids to meet their energy demands. These cells are rich in mitochondria and peroxisomes, the two organelles that mediate fatty acid oxidation. Emerging evidence shows that both fatty acid pathways are regulated by reversible posttranslational modifications, particularly by lysine acylation. Sirtuin 5 (Sirt5), which localizes to both mitochondria and peroxisomes, reverses post-translational lysine acylation on several enzymes involved in fatty acid oxidation. However, the role of the Sirt5 in regulating kidney energy metabolism has yet to be determined. We subjected male Sirt5-deficient mice (either +/- or -/-) and wild-type controls, as well as isolated proximal tubule cells, to two different AKI models (ischemia-induced or cisplatin-induced AKI). We assessed kidney function and injury with standard techniques and measured fatty acid oxidation by the catabolism of Sirt5 was highly expressed in proximal tubular epithelial cells. At baseline, Our findings indicate that Sirt5 regulates the balance of mitochondrial versus peroxisomal fatty acid oxidation in proximal tubular epithelial cells to protect against injury in AKI. This novel mechanism might be leveraged for developing AKI therapies.
Sections du résumé
BACKGROUND
The primary site of damage during AKI, proximal tubular epithelial cells, are highly metabolically active, relying on fatty acids to meet their energy demands. These cells are rich in mitochondria and peroxisomes, the two organelles that mediate fatty acid oxidation. Emerging evidence shows that both fatty acid pathways are regulated by reversible posttranslational modifications, particularly by lysine acylation. Sirtuin 5 (Sirt5), which localizes to both mitochondria and peroxisomes, reverses post-translational lysine acylation on several enzymes involved in fatty acid oxidation. However, the role of the Sirt5 in regulating kidney energy metabolism has yet to be determined.
METHODS
We subjected male Sirt5-deficient mice (either +/- or -/-) and wild-type controls, as well as isolated proximal tubule cells, to two different AKI models (ischemia-induced or cisplatin-induced AKI). We assessed kidney function and injury with standard techniques and measured fatty acid oxidation by the catabolism of
RESULTS
Sirt5 was highly expressed in proximal tubular epithelial cells. At baseline,
CONCLUSIONS
Our findings indicate that Sirt5 regulates the balance of mitochondrial versus peroxisomal fatty acid oxidation in proximal tubular epithelial cells to protect against injury in AKI. This novel mechanism might be leveraged for developing AKI therapies.
Identifiants
pubmed: 31575700
pii: ASN.2019020163
doi: 10.1681/ASN.2019020163
pmc: PMC6900790
doi:
Substances chimiques
Fatty Acids
0
SIRT5 protein, mouse
0
Sirtuins
EC 3.5.1.-
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2384-2398Subventions
Organisme : NIDDK NIH HHS
ID : R56 DK121758
Pays : United States
Organisme : NIH HHS
ID : S10 OD016281
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK079307
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK121758
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK120531
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK090242
Pays : United States
Informations de copyright
Copyright © 2019 by the American Society of Nephrology.
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