Mitochondrial biogenesis induced by the β2-adrenergic receptor agonist formoterol accelerates podocyte recovery from glomerular injury.
Adrenergic beta-2 Receptor Agonists
/ pharmacology
Animals
Apoptosis
/ drug effects
Cell Line
Disease Models, Animal
Doxorubicin
/ toxicity
Formoterol Fumarate
/ pharmacology
Gene Knockdown Techniques
Glomerulonephritis
/ chemically induced
Humans
Mice
Mitochondria
/ drug effects
Organelle Biogenesis
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
/ metabolism
Podocytes
/ cytology
Receptors, Adrenergic, beta-2
/ genetics
Signal Transduction
albuminuria
focal segmental glomerulosclerosis
glomerulonephritis
glomerulus
podocyte
Journal
Kidney international
ISSN: 1523-1755
Titre abrégé: Kidney Int
Pays: United States
ID NLM: 0323470
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
06
01
2019
revised:
07
03
2019
accepted:
28
03
2019
pubmed:
3
7
2019
medline:
21
10
2020
entrez:
3
7
2019
Statut:
ppublish
Résumé
Podocytes have limited ability to recover from injury. Here, we demonstrate that increased mitochondrial biogenesis, to meet the metabolic and energy demand of a cell, accelerates podocyte recovery from injury. Analysis of events induced during podocyte injury and recovery showed marked upregulation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a transcriptional co-activator of mitochondrial biogenesis, and key components of the mitochondrial electron transport chain. To evaluate our hypothesis that increasing mitochondrial biogenesis enhanced podocyte recovery from injury, we treated injured podocytes with formoterol, a potent, specific, and long-acting β2-adrenergic receptor agonist that induces mitochondrial biogenesis in vitro and in vivo. Formoterol increased mitochondrial biogenesis and restored mitochondrial morphology and the injury-induced changes to the organization of the actin cytoskeleton in podocytes. Importantly, β2-adrenergic receptors were found to be present on podocyte membranes. Their knockdown attenuated formoterol-induced mitochondrial biogenesis. To determine the potential clinical relevance of these findings, mouse models of acute nephrotoxic serum nephritis and chronic (Adriamycin [doxorubicin]) glomerulopathy were used. Mice were treated with formoterol post-injury when glomerular dysfunction was established. Strikingly, formoterol accelerated the recovery of glomerular function by reducing proteinuria and ameliorating kidney pathology. Furthermore, formoterol treatment reduced cellular apoptosis and increased the expression of the mitochondrial biogenesis marker PGC-1α and multiple electron transport chain proteins. Thus, our results support β2-adrenergic receptors as novel therapeutic targets and formoterol as a therapeutic compound for treating podocytopathies.
Identifiants
pubmed: 31262488
pii: S0085-2538(19)30458-2
doi: 10.1016/j.kint.2019.03.023
pmc: PMC6708766
mid: NIHMS1528670
pii:
doi:
Substances chimiques
ADRB2 protein, human
0
ADRB2 protein, mouse
0
Adrenergic beta-2 Receptor Agonists
0
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
0
Ppargc1a protein, mouse
0
Receptors, Adrenergic, beta-2
0
Doxorubicin
80168379AG
Formoterol Fumarate
W34SHF8J2K
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
656-673Subventions
Organisme : NIEHS NIH HHS
ID : P30 ES006694
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK120510
Pays : United States
Organisme : NIDDK NIH HHS
ID : F31 DK105782
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK087956
Pays : United States
Organisme : NIDDK NIH HHS
ID : R56 DK116887
Pays : United States
Informations de copyright
Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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