대한신장학회

논문분류	춘계학술대회 초록집
제목	TG2 Inhibitors Alleviate Indoxyl Sulfate-Induced Fibrosis in Muscle Cell
저자	Soeun Yun
출판정보	2025; 2025(1):
키워드	Indoxyl sulfate (IS), chronic kidney disease (CKD), muscle dysfunction, oxidative stress, Transglutaminase 2 (TG2)
초록	Indoxyl sulfate (IS), a uremic toxin associated with chronic kidney disease (CKD), induces muscle dysfunction through fibrosis, mitochondrial dysfunction, oxidative stress and senescence. The TG2 inhibitors have emerged as potential therapeutic agents. However, their specific involvement in IS-induced modulation of muscle cells remains unclear. Therefore, clarifying the consequences of IS and the therapeutic relevance of TG2 inhibitors to design novel strategies against CKD-associated muscle dysfunction is crucial. C2C12 muscle cells were treated with IS at concentrations of 53 μg/mL and 106 μg/mL for 48 hours to simulate uremic toxin exposure. TG2 inhibitors (iTG2) were then added at 0.25 mM, 0.5 mM. mRNA sequencing was performed to analyze gene expression patterns associated with fibrosis, senescence, mitochondrial function, and oxidative stress. The sequencing data were processed using Gene Ontology (GO) term filtering, hierarchical clustering, and KEGG pathway analysis to pinpoint affected molecular pathways. GO term analysis and expression pattern revealed that IS exposure strongly enriched oxidative stress-related terms and suppressed expression of antioxidant genes such as MSRA, CCS, BECN1, and APOD. Downregulation of PIM1, COQ4, and ATP biosynthesis genes indicated mitochondrial dysfunction. Increased expression of fibrosis markers (COL1A1, COL5A1, FN1) and senescence genes (CDKN1A, SRF) suggested ECM remodeling and stress-induced aging. KEGG analysis indicated upregulated ECM-receptor interaction, focal adhesion, and PI3K-AKT, which all may contribute to fibrosis. These effects were partially rescued by TG2 inhibition (iTG2), evidenced by restoration of antioxidant gene expression, improved mitochondrial function, and reduced fibrotic markers. Western blot analysis confirmed that iTG2 reduced the levels of fibronectin (FN), intercellular adhesion molecule-1 (ICAM-1), and beta-galactosidase. Additionally, ROS assay results demonstrated that TG2 inhibition significantly decreased oxidative stress. IS induces oxidative stress-mediated muscle dysfunction, that cause fibrosis, mitochondria dysfunction, and cellular senescence. Inhibition of TG2 circumvents these effects, indicating a potential therapeutic strategy to counteract ROS-induced muscle loss in CKD.
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