Abstract
Sustained injury to renal tubular epithelial cells (TECs), driven by excessive autophagy, is a critical mechanism underlying kidney fibrosis. Our previous work identified JLP—a TEC-expressed scaffolding protein—as an endogenous anti-fibrotic factor that counteracts TGF-β1–induced autophagy and fibrogenesis. However, the mechanism underlying JLP downregulation in renal fibrosis remains unclear. Here, we delineated a TGF-β1/LEF1/β-catenin/JLP axis that governed TEC autophagy through a dichotomous regulatory circuit. Under physiological conditions, low levels of β-catenin and LEF1 with minimal nuclear localization permit normal JLP expression, which in turn maintains autophagy in check. In contrast, during renal injury, TGF-β1 promoted the expression and nuclear translocation of β-catenin and LEF1, which together suppressed JLP transcription. This loss of JLP-mediated inhibition led to unchecked autophagy and exacerbated fibrotic damage. Analyses of kidney tissues from patients with CKD, murine fibrotic kidneys, and cultured HK-2 cells confirmed consistent JLP downregulation accompanied by upregulation and nuclear accumulation of LEF1 and β-catenin. Therapeutic intervention using the β-catenin/LEF1 inhibitor iCRT3 or LEF1-targeted silencing in murine fibrosis models restored JLP expression, attenuated TEC autophagy, and ameliorated renal fibrosis. These findings revealed an autoregulatory circuit controlling TEC autophagy and fibrogenesis, and supported LEF1 and β-catenin as potential therapeutic targets in CKD.
Authors
Chen Li, Meng Zhang, Maoqing Tian, Zeyu Tang, Yuying Hu, Yuyu Long, Xiaofei Wang, Liwen Qiao, Jiefei Zeng, Yujuan Wang, Xinghua Chen, Cheng Chen, Xiaoyan Li, Lu Zhang, Huiming Wang
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