Significance Albuminuria is the hallmark of nephrotic syndrome (NS), a leading cause of chronic kidney disease affecting 500 million people worldwide. Thus, there is a clear need to discover novel… Click to show full abstract
Significance Albuminuria is the hallmark of nephrotic syndrome (NS), a leading cause of chronic kidney disease affecting 500 million people worldwide. Thus, there is a clear need to discover novel drug targets to treat proteinuric kidney disease. We demonstrate that thioredoxin-interacting protein (TXNIP), a redox protein that forms the complex with antioxidant oxidoreductase thioredoxin (Trx), relocates from nucleus to mitochondria when C/EBP homologous protein (CHOP), a major endoplasmic reticulum (ER) stress-associated transcription factor, is induced by albuminuria. TXNIP shuttling to mitochondria is essential for mitochondrial reactive oxygen species (ROS) production, which oxidizes mitochondrial-specific Trx2 and disrupts the association between Trx2-TXNIP and Trx2-ASK1 in mitochondria, leading to NLRP3 inflammasome activation and mitochondria-dependent apoptosis. Thus, TXNIP is a potential target to treat NS.
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Year Published: 2022
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