ATF4 promotes renal tubulointerstitial fibrosis through hexokinase II-mediated glycolysis

作者：Songtao Feng, Yue-Ming Gao, Zheng Wang, Wei‐Jie Ni, Yan Zhou, Mingyue Yuan, Junbo Ge, Lu Sun, Bi-Cheng Liu, Hui Qian, Zuo‐Lin Li · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1683249 · 被引用次数：3 · 研究领域：Chronic Kidney Disease and Diabetes、Kidney Stones and Urolithiasis Treatments、Ion Transport and Channel Regulation

Background Renal tubulointerstitial fibrosis is a reliable predictor of progressive chronic kidney disease (CKD). Activating transcription factor 4 (ATF4) has recently emerged as a pivotal player in multiple pathophysiologic processes, particularly the stress response processes. This study aims to explore the role of ATF4 in tubulointerstitial fibrosis from a metabolic perspective. Methods A murine model of renal fibrosis was generated via unilateral ureteral obstruction (UUO). Quantitative PCR was employed to assess the expression of inflammation-related genes and fibrotic markers in renal tissue, while Western blotting was used to quantify the corresponding protein levels. Immunohistochemistry was performed to determine the localization and expression patterns of ATF4. Lentivirus-mediated ATF4 knockdown mice, along with mice subjected to glycolytic inhibition, were subsequently employed to further investigate their effects on inflammatory mediators and fibrotic markers. In parallel, human renal proximal tubule epithelial cells (HK-2) were exposed to transforming growth factor-β1 (TGF-β1) to induce fibrosis in vitro . Subsequent molecular assays were performed to confirm the regulatory relationship between ATF4 and hexokinase II (HK-II), including verification of ATF4 binding to the HK2 promoter. Results Western blotting and PCR analyses revealed a pronounced elevation of inflammatory cytokines, fibrotic markers, and ATF4 in the renal tissues of UUO mice compared with sham c...