4.7 Article

Kidney tubular epithelial cells control interstitial fibroblast fate by releasing TNFAIP8-encapsulated exosomes

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CELL DEATH & DISEASE
卷 14, 期 10, 页码 -

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SPRINGERNATURE
DOI: 10.1038/s41419-023-06209-w

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This study found that exosomes derived from stressed/injured tubules play a pivotal role in regulating fibroblast apoptosis and fate. Exosomal-TNFAIP8 promotes p53 degradation, thereby inhibiting fibroblast apoptosis and inducing their proliferation.
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-beta 1, they produced and released increased amounts of exosomes (TGF beta-Exo), which prevented renal interstitial fibroblasts from apoptosis. In vivo, injections of TGF beta-Exo promoted renal fibroblast survival, whereas blockade of exosome secretion accelerated fibroblast apoptosis in obstructive nephropathy. Proteomics profiling identified the tumor necrosis factor-alpha-induced protein 8 (TNFAIP8) as a key component enriched in TGF beta-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 TGF beta-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.

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