Translational research : the journal of laboratory and clinical medicine · 2026
Activating transcription factor 3 aggravates renal fibrosis by regulating EGR2-mediated autophagy.
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Yan Ruiwei, Song Anni, Hu Mingcun, Yin Xingjie, Xiong Wei, Gao Pan, Zhang Chun
Аннотация
BACKGROUND: Chronic kidney disease (CKD) affects approximately 10% of global populations, pathologically characterized by renal fibrosis including extracellular matrix (ECM) deposition and renal tubular atrophy. Emerging evidence suggests that autophagy plays a crucial role in renal fibrosis, but the regulatory mechanisms are still not well understood.
PURPOSES: In this study, we try to explore the role of activating transcription factor 3 (ATF3) in renal fibrosis as well as the potential mechanisms.
METHODS: We utilized two CKD mouse models to confirm the expression of ATF3 via immunohistochemistry staining, western blot or real-time quantitative polymerase chain reaction (RT-qPCR). Then, ATF3 knockdown mice were constructed to investigate its impact on renal fibrosis by adeno-associated virus (AAV) administration. Additionally, transcriptomic analyses and in vitro experiments were performed in The Boston University mouse proximal tubular (BUMPT) cell lines to evaluate the possible downstream signaling pathways.
RESULTS: Our results demonstrated that the expression of ATF3 was significantly increased in kidney specimens from both unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI) mice. Knockdown of ATF3 attenuated ECM deposition and epithelial-mesenchymal transition (EMT) in vivo and vitro. Autophagy was indicated to be involved in ATF3-mediated renal fibrosis by transcriptomic analyses, which was verified by genetic deletion of ATF3 in BUMPT cells. Besides, the database indicated that early growth response protein 2 (EGR2), a potent profibrotic molecule proven previously, was suggested to be transcriptionally activated by ATF3, which was partially confirmed by in vitro experiments.
CONCLUSIONS: Collectively, enhanced expression of ATF3 exerts a detrimental effect in renal fibrosis by regulating EGR2-mediated autophagy pathways.
PURPOSES: In this study, we try to explore the role of activating transcription factor 3 (ATF3) in renal fibrosis as well as the potential mechanisms.
METHODS: We utilized two CKD mouse models to confirm the expression of ATF3 via immunohistochemistry staining, western blot or real-time quantitative polymerase chain reaction (RT-qPCR). Then, ATF3 knockdown mice were constructed to investigate its impact on renal fibrosis by adeno-associated virus (AAV) administration. Additionally, transcriptomic analyses and in vitro experiments were performed in The Boston University mouse proximal tubular (BUMPT) cell lines to evaluate the possible downstream signaling pathways.
RESULTS: Our results demonstrated that the expression of ATF3 was significantly increased in kidney specimens from both unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI) mice. Knockdown of ATF3 attenuated ECM deposition and epithelial-mesenchymal transition (EMT) in vivo and vitro. Autophagy was indicated to be involved in ATF3-mediated renal fibrosis by transcriptomic analyses, which was verified by genetic deletion of ATF3 in BUMPT cells. Besides, the database indicated that early growth response protein 2 (EGR2), a potent profibrotic molecule proven previously, was suggested to be transcriptionally activated by ATF3, which was partially confirmed by in vitro experiments.
CONCLUSIONS: Collectively, enhanced expression of ATF3 exerts a detrimental effect in renal fibrosis by regulating EGR2-mediated autophagy pathways.