Frontiers in physiology · 2026
A comprehensive approach to elucidating the pathophysiology of kidney fibrosis based on extracellular vesicle proteomics.
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Kim Yaerim, Kim Kyuhyeon, Park Hong-Beom, Lee Sunwha, Yu Mi-Yeon, Kim Young Joo, Choi Soo Bin, Park Woo Yeong, Jin Kyubok, Kim Dong Ki, Kim Yon Su, Han Dohyun, Yang Seung Hee
Аннотация
INTRODUCTION: Transglutaminase 2 (TG2) plays a profibrotic role in chronic kidney disease (CKD), but its role in the exosomal proteome remains unexplored. Here, we aimed to evaluate biological processes specifically involved in CKD progression through exosomal proteomic profiling following TG2 inhibition.
MATERIALS AND METHODS: Human proximal tubular epithelial cells (hPTECs) were treated with recombinant transforming growth factor-β (rTGF-β) to induce fibrosis and cysteamine to inhibit TG2. A unilateral ureteral obstruction (UUO) mouse model was used for in vivo validation. EVs were isolated and analyzed using LC-MS/MS analysis. Bioinformatics tools, including enrichGO and STRING, were used to identify key biological pathways and protein interactions. Findings were validated in the UUO mouse model.
RESULTS: TG2 inhibition attenuated the expression of fibrosis- and inflammation-associated proteins in hPTECs and fibroblasts. EV proteomic analysis revealed distinct protein expression patterns following rTGF-β treatment and TG2 inhibition. Altered proteins were primarily extracellular matrix components such as connective tissue growth factor, IGF-binding protein, laminin, plasminogen activator inhibitor, periostin, and collagen.
CONCLUSIONS: TG2 inhibition modulated EV-associated proteins involved in fibrosis and inflammation, highlighting its therapeutic potential in CKD. Identifying reversible fibrosis-related factors may provide new targets for CKD treatment.
MATERIALS AND METHODS: Human proximal tubular epithelial cells (hPTECs) were treated with recombinant transforming growth factor-β (rTGF-β) to induce fibrosis and cysteamine to inhibit TG2. A unilateral ureteral obstruction (UUO) mouse model was used for in vivo validation. EVs were isolated and analyzed using LC-MS/MS analysis. Bioinformatics tools, including enrichGO and STRING, were used to identify key biological pathways and protein interactions. Findings were validated in the UUO mouse model.
RESULTS: TG2 inhibition attenuated the expression of fibrosis- and inflammation-associated proteins in hPTECs and fibroblasts. EV proteomic analysis revealed distinct protein expression patterns following rTGF-β treatment and TG2 inhibition. Altered proteins were primarily extracellular matrix components such as connective tissue growth factor, IGF-binding protein, laminin, plasminogen activator inhibitor, periostin, and collagen.
CONCLUSIONS: TG2 inhibition modulated EV-associated proteins involved in fibrosis and inflammation, highlighting its therapeutic potential in CKD. Identifying reversible fibrosis-related factors may provide new targets for CKD treatment.