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Keratin 20 Suppresses Exosomal Secretion of Peroxiredoxin 2 and Ferroptosis in Acute Kidney Injury

分泌物 急性肾损伤 医学 内科学 细胞生物学 生物
作者
Lijun Yin,Zebin Deng,Jiachen Liu,Ye Lin,Jun Huang,Yingbo Dai,Yinhuai Wang,Li Yu,Xuejing Zhu,Yu Lu,Yong Wu,Baiyu Feng,Yong He,Dongshan Zhang,Shao-Bin Duan,Zheng Dong,Fei Deng,Anqun Chen
出处
期刊:Journal of The American Society of Nephrology 卷期号:37 (1): 18-35
标识
DOI:10.1681/asn.0000000805
摘要

Key Points Keratin 20 was upregulated earlier than kidney injury molecule 1 in AKI, and its proximal tubule–specific deletion aggravated kidney dysfunction in mouse models. Keratin 20 competed with apoptosis-linked gene-2-interacting protein X for peroxiredoxin 2 binding, thereby decreasing the exosomal secretion of peroxiredoxin 2 and inhibiting ferroptosis in kidney tubular cells. Background AKI is a prevalent clinical syndrome with insufficient kidney function. Keratin 20 (KRT20), a component of intermediate filaments, is widely recognized as a biomarker of kidney tubular injury, yet its exact function in kidney disease remains uncertain. Methods RNA sequencing data from a mouse model of ischemia/reperfusion-induced AKI were analyzed to assess KRT20 transcript levels. The effect of specific Krt20 knockout in renal proximal tubule cells ( Krt20 PTKO ) was subsequently examined in two distinct AKI mouse models. Luciferase reporter assays and chromatin immunoprecipitation–PCR was used to identify transcription factors regulating KRT20 expression, whereas immunoprecipitation followed by mass spectrometry elucidated the downstream targets of KRT20. In addition, the clinical significance of KRT20 and peroxiredoxin 2 (PRDX2) was evaluated in patients with acute tubular necrosis. Results KRT20 was significantly upregulated in renal proximal tubule cells during the early phase of AKI, preceding the induction of kidney injury molecule 1 expression. This upregulation was mediated by FBJ Murine Osteosarcoma Viral Oncogene Homolog B in both ischemia/reperfusion and cisplatin-induced AKI models. Renal proximal tubule cell–specific knockout of Krt20 exacerbated the kidney injury during AKI. Mechanistically, KRT20 protected against AKI by sequestering PRDX2, an antioxidant protein, and inhibiting the exosomal secretion of PRDX2, eventually preventing ferroptosis in kidney tubular cells. Further analysis revealed that apoptosis-linked gene-2-interacting protein X facilitated PRDX2 exosomal release, whereas KRT20 competed with apoptosis-linked gene-2-interacting protein X for binding to the N -terminal domain of PRDX2, thereby retaining PRDX2 intracellularly. Finally, the expression levels of KRT20 and PRDX2 were correlated with kidney injury severity and kidney function decline in clinical samples. Conclusions These findings indicate that KRT20 was upregulated in the early stages of AKI, serving to protect kidney tubule cells by sequestering PRDX2 and inhibiting ferroptosis.
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