INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
You Zhou,You Wu,Rui Zhu
Background Septic acute kidney injury (S-AKI) is a major cause of acute kidney injury (AKI), but no effective therapies exist to prevent or treat it. Although KLF6 is linked to various pathophysiological processes, its exact role in S-AKI is not yet fully understood. Methods The role of KLF was investigated using both the mouse CLP model and in vitro systems. To identify the transcriptional targets regulated by KLF6, ChIP-qPCR and luciferase reporter assays were carried out. Biochemical and cellular techniques were employed to assess cellular injury and lipid peroxidation levels. The extent of ferroptosis was evaluated through transmission electron microscopy (TEM). Results KLF6 levels were significantly increased in a renal IRI model. Knockdown of KLF6 using AAV9 reduced kidney injury in both in vitro and in vivo models, while KLF6 overexpression aggravated injury. Overexpression of KLF6 promoted ferroptosis, whereas its knockdown reduced lipid peroxidation and ferroptosis. KLF6 regulates NCOA4 expression by binding to its promoter, controlling ferroptosis. Knockdown of NCOA4 in vitro alleviated ferroptosis and cellular damage caused by KLF6 overexpression. Pharmacological inhibition of KLF6 reduced kidney injury and ferroptosis in S-AKI mice. Conclusion Our study uncovered a previously unrecognized role for KLF6 in S-AKI. By facilitating NCOA4 transcription, KLF6 intensified ferroptosis, which, in turn, aggravated septic AKI.
研究领域:
肾脏病学
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分子生物学
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病理生理学
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细胞生物学
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转录调控
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
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2024
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IF 6.7
Yu-Qing Li,Xin-Ming Yu,Xue-Mei Shang,Jing-Yi Lin,Rui-Zhi Tan,Jian-Chun Li,Hong-Wei Su,Hong-Ping Shen,Hong-Lian Wang,Li Wang
Background Renal fibrosis is a hallmark of chronic kidney disease (CKD). Smad3 serves as the principal transcription factor mediating the pro-fibrosis effects of TGF-β signaling in renal fibrosis. Biochanin A (BCA), a natural isoflavone, has been shown to attenuate renal fibrosis by inhibiting TGF-β signaling but the detailed mechanisms remain unresolved. This study aimed to elucidate the specific mechanisms by which BCA modulates TGF-β signaling. Methods Renal fibrosis models were established both in vitro , using TGF-β1-stimulated mouse renal tubular TCMK1 cells, and in vivo , employing mice with unilateral ureter obstruction (UUO). RNA-seq was conducted to identify BCA-regulated genes. The AnimalTFDB4.0 database was utilized to predict transcription factors with potential binding to Smad3 promoter. The activities of TGF-β signaling and the cloned mouse Smad3 promoter were assessed using luciferase reporter assays. Plasmid transfection was performed using polyethylenimine in TCMK1 cells or ultrasound microbubbles in UUO kidneys. Gene expression was analyzed by RT-PCR, western blot, and immunohistochemistry assays. Results BCA significantly inhibited TGF-β signaling activity and suppressed TGF-β1-induced fibrotic gene expression in TCMK1 cells. RNA-seq and in silico analyses identified Smad3 as the key gene downregulated by BCA, while leaving Smad2 unaffected. This selective transcriptional suppression of Smad3 by BCA was validated by luciferase reporter assays using the cloned Smad3 promoter. Furthermore, transcription factor binding prediction identified that Klf6, a transcription factor downregulated by BCA, has binding potential to the Smad3 promoter and promotes Smad3 transcription. Klf6 expression was induced in TGF-β1-stimulated TCMK1 cells and UUO kidneys, but this induction was abolished upon BCA treatment. Importantly, Klf6 overexpression restored Smad3 expression and counteracted the anti-fibrosis effects of BCA in both TGF-β1-stimulated TCMK1 cells and UUO kidneys. Conclusion TGF-β-responsive Klf6 transcriptionally transactivates Smad3 expression. BCA exerts anti-renal fibrosis effects by inhibiting the Klf6-Smad3 signaling axis, underscoring its therapeutic potential in the treatment of CKD.
研究领域:
药理学
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分子生物学
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肾病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELLULAR SIGNALLING
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2024
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IF 4.4
Jingwen Shi,Wenda Jing,Yueyun He,Ying Huang
Despite decades of research, endometriosis remains a mysterious gynecological disease with unknown etiology and pathogenesis. Krüppel-like Factor 6 (KLF6), a transcription factor, has a wide expression profile and regulates a variety of biological processes. Here, we investigated the expression and function of KLF6 and its possible regulatory mechanisms in endometriosis. To determine the function of KLF6, knockdown and overexpression experiments were performed in eutopic endometrial stromal cells (EU-ESCs) and ectopic endometrial stromal cells (EC-ESCs), respectively. Cell viability, apoptosis, migration, invasion, and angiogenesis assays were conducted in ESCs. ChIP-sequencing and mRNA-sequencing were performed to investigate the functional mechanism of KLF6 in regulating ESCs. We found that KLF6 was highly expressed in eutopic endometrium of endometriosis patients, compared with ectopic endometrium. Similarly, the same was true in EU-ESCs, which was compared with EC-ESCs. Overexpression of KLF6 significantly suppressed EC-ESC proliferation, migration and invasion and induced cell apoptosis, while knockdown of KLF6 resulted in the opposite effects on EU-ESCs. Overexpression of KLF6 significantly inhibited EC-ESC angiogenesis. Mechanistically, the results of ChIP sequencing and mRNA sequencing revealed that CTNNB1 may be a transcriptional target regulated by KLF6. Reintroduction of KLF6 reversed the effects of KLF6 knockdown on EU-ESCs. KLF6 inhibited the proliferation, migration and angiogenesis of EC-ESCs by inhibiting the expression of CTNNB1. Our findings provided a new perspective on the role of KLF6 in endometriosis progression and inspire potential targeted therapeutic strategies.
研究领域:
妇科学
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分子生物学
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转录因子
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疾病发病机制
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2025
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IF 4.7
Fengjie Zhang,Shiyu Hu,Yuyuan Ying,Meiru Zhou,Xunuo Wen,Qingru Sun,Zhaohuan Lou,Jianli Gao
Thymus is the core organ that reflects the degree of aging, and the anti-aging effect of rapamycin(RAPA) has been confirmed by multiple studies, but the dynamic changes of the thymus after the administration of RAPA have been lacking systematic research. Here, we observed the involution of thymus induced by RAPA (1 mg/kg/day, i.p. for 3 days) and its regeneration kinetics after withdrawal of RAPA, to explore the possible mechanism of RAPA’s anti-aging effects based on changes in thymus function. The results show that the thymus weight decreased by 46.15% post-RAPA, then regenerated from 20.45 mg to 57.97 mg, reaching 1.3-fold baseline levels in age-matched controls. RAPA can cause acute involution in thymic structure and function, such as loss of medullary thymic epithelial cells (mTECs) and subcapsular thymic epithelial cells (sTECs), abnormal differentiation of thymocytes, reduction of peripheral T cell proportion, and up-regulation of Foxn1 and Klf6 mRNA levels. Regeneration featured expanded double positive (DP) T cells, CD3 + TCRβ + T cells, CD8 single-positive (SP) T cells, medullary dilatation, and thymocyte telomere elongation. IL-7 and MET have pro-regeneration effects, but neither of them could accelerate RAPA-mediated thymic regeneration. IL-7 can prolong telomere length of thymocytes and restore peripheral T cell homeostasis, while MET can promote T cell positive selection and increase Sirt3 and Gimap4 mRNA levels. These results demonstrate that RAPA triggers transient thymic suppression followed by thymus volume and functional recovery. It seems that RAPA-mediated immune reconstitution may be an important reason for the potential anti-aging effect of RAPA.
研究领域:
免疫学
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衰老研究
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药理学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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