Kidney tubular epithelial cells control interstitial fibroblast fate by releasing TNFAIP8-encapsulated exosomes.
Humans
Epithelial Cells
/ metabolism
Exosomes
/ metabolism
Fibroblasts
/ metabolism
Fibrosis
Kidney
/ pathology
Kidney Tubules
/ pathology
Renal Insufficiency, Chronic
/ pathology
Transforming Growth Factor beta
/ metabolism
Tumor Suppressor Protein p53
/ metabolism
Apoptosis Regulatory Proteins
/ metabolism
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
12 10 2023
12 10 2023
Historique:
received:
20
01
2023
accepted:
02
10
2023
revised:
18
09
2023
medline:
1
11
2023
pubmed:
13
10
2023
entrez:
12
10
2023
Statut:
epublish
Résumé
Kidney fibrosis, characterized by the activation and expansion of the matrix-producing fibroblasts, is the common outcome of chronic kidney disease (CKD). While fibroblast proliferation is well studied in CKD, little is known about the regulation and mechanism of fibroblast depletion. Here, we show that exosomes derived from stressed/injured tubules play a pivotal role in dictating fibroblast apoptosis and fate. When human kidney tubular cells (HK-2) were stimulated with TGF-β1, they produced and released increased amounts of exosomes (TGFβ-Exo), which prevented renal interstitial fibroblasts from apoptosis. In vivo, injections of TGFβ-Exo promoted renal fibroblast survival, whereas blockade of exosome secretion accelerated fibroblast apoptosis in obstructive nephropathy. Proteomics profiling identified the tumor necrosis factor-α-induced protein 8 (TNFAIP8) as a key component enriched in TGFβ-Exo. TNFAIP8 was induced in renal tubular epithelium and enriched in the exosomes from fibrotic kidneys. Knockdown of TNFAIP8 in tubular cells abolished the ability of TGFβ-Exo to prevent fibroblast apoptosis. In vivo, gain- or loss- of TNFAIP8 prevented or aggravated renal fibroblast apoptosis after obstructive injury. Mechanistically, exosomal-TNFAIP8 promoted p53 ubiquitination leading to its degradation, thereby inhibiting fibroblasts apoptosis and inducing their proliferation. Collectively, these results indicate that tubule-derived exosomes play a critical role in controlling the size of fibroblast population during renal fibrogenesis through shuttling TNFAIP8 to block p53 signaling. Strategies to target exosomes may be effective strategies for the therapy of fibrotic CKD.
Identifiants
pubmed: 37828075
doi: 10.1038/s41419-023-06209-w
pii: 10.1038/s41419-023-06209-w
pmc: PMC10570316
doi:
Substances chimiques
Transforming Growth Factor beta
0
Tumor Suppressor Protein p53
0
TNFAIP8 protein, human
0
Apoptosis Regulatory Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
672Informations de copyright
© 2023. The Author(s).
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