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Wnt/β-catenin/ATF3 signaling promotes AKI to CKD progression by regulating mitophagy in mice [HKC-8]

ABSTRACT: Sustained activation of Wnt/β-catenin signaling has been shown to promote AKI to CKD progression. However, its underlying mechanisms remain largely unclear. In this study, we investigated this issue via unilateral ischemia/reperfusion injury in mice and hypoxia/reoxygenation (H/R) in HKC-8 cells. Both in vitro and in vivo, overexpression of Wnt1 promoted mitochondrial dynamics and mitophagy damage. Furthermore, we revealed that ATF3 not only is a transcriptional target of canonical Wnt/β-catenin signaling but is also an important pathogenic mediator of kidney disease. ATF3 was expressed in various CKD animal models, including UUO, UIRI, ADR and 5/6NX. In vitro, exogenous ATF3 induced mitochondrial dynamics and mitophagy, and silenced ATF3 expression protected mitochondrial function. Finally, compared with normal individuals, patients with various kidney diseases presented markedly elevated levels of ATF3. In addition, ATF3 levels are closely correlated with renal injury markers and renal fibrosis area in patients. Thus, these results suggest that Wnt/β-catenin/ATF3 signaling activation promotes AKI to CKD progression by regulating mitochondrial dynamics and mitophagy. ATF3 can serve as a promising potential biomarker for AKI to CKD progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285716 | GEO | 2026/01/01

REPOSITORIES: GEO

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Project description:Tumor: tumor microenvironment (TME) interactions are critical for tumor progression and the composition and structure of the local extracellular matrix (ECM) are key determinants of tumor metastasis. We recently reported that activation of Wnt/beta- catenin signaling in Ewing sarcoma cells induces widespread transcriptional changes that are associated with acquisition of a metastatic tumor phenotype. Significantly, ECM protein-encoding genes were found to be enriched among Wnt/beta-catenin induced transcripts, leading us to hypothesize that activation of canonical Wnt signaling might induce changes in the Ewing sarcoma secretome. To address this hypothesis, conditioned media from Ewing sarcoma cell lines cultured in the presence or absence of Wnt3a was collected for proteomic analysis. Label-free mass spectrometry was used to identify and quantify differentially secreted proteins. We then used in silico databases to identify only proteins annotated as secreted. Comparison of the secretomes of two Ewing sarcoma cell lines revealed numerous shared proteins, as well as a degree of heterogeneity, in both basal and Wnt-stimulated conditions. Gene set enrichment analysis of secreted proteins revealed that Wnt stimulation reproducibly resulted in increased secretion of proteins involved in ECM organization, ECM receptor interactions, and collagen formation. In particular, Wnt-stimulated Ewing sarcoma cells upregulated secretion of structural collagens, as well as matricellular proteins, such as the metastasis-associated protein, tenascin C (TNC). Interrogation of published databases confirmed reproducible correlations between Wnt/beta-catenin activation and TNC and COL1A1 expression in patient tumors. In summary, this first study of the Ewing sarcoma secretome reveals that Wnt/beta-catenin activated tumor cells upregulate secretion of ECM proteins. Such Wnt/beta-catenin mediated changes are likely to impact on tumor: TME interactions that contribute to metastatic progression.

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Wnt/β-catenin/ATF3 signaling promotes AKI to CKD progression by regulating mitophagy in mice [HKC-8]

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