Inhibiting Transglutaminase 2 Mediates Kidney Fibrosis via Anti-Apoptosis

Moon, Jong-Joo; Choi, Yejin; Kim, Kyu-Hyeon; Seo, Areum; Kwon, Soie; Kim, Yong-Chul; Kim, Yon Su; Kim, Yon-Su; Yang, Seung-Hee

doi:10.3390/biomedicines10061345

Cited by 7 publications

(4 citation statements)

References 61 publications

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“…Immunohistochemical images were captured using a Leica inverted light microscope (Leica Camera, Wetzlar, Germany). The degree of fibrosis and the positive area of primary antibodies for five fields was scored quantitatively using the LAS‐4000 program (Lecia Camera, Germany) 30 …”

Section: Methodsmentioning

confidence: 99%

Protective effect of Cyclo(His‐Pro) on peritoneal fibrosis through regulation of HDAC3 expression

Kim,

Han,

Kim

et al. 2024

The FASEB Journal

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Peritoneal dialysis is a common treatment for end‐stage renal disease, but complications often force its discontinuation. Preventive treatments for peritoneal inflammation and fibrosis are currently lacking. Cyclo(His‐Pro) (CHP), a naturally occurring cyclic dipeptide, has demonstrated protective effects in various fibrotic diseases, yet its potential role in peritoneal fibrosis (PF) remains uncertain. In a mouse model of induced PF, CHP was administered, and quantitative proteomic analysis using liquid chromatography–tandem mass spectrometry was employed to identify PF‐related protein signaling pathways. The results were further validated using human primary cultured mesothelial cells. This analysis revealed the involvement of histone deacetylase 3 (HDAC3) in the PF signaling pathway. CHP administration effectively mitigated PF in both peritoneal tissue and human primary cultured mesothelial cells, concurrently regulating fibrosis‐related markers and HDAC3 expression. Moreover, CHP enhanced the expression of nuclear factor erythroid 2‐related factor 2 (Nrf2) while suppressing forkhead box protein M1 (FOXM1), known to inhibit Nrf2 transcription through its interaction with HDAC3. CHP also displayed an impact on spleen myeloid‐derived suppressor cells, suggesting an immunomodulatory effect. Notably, CHP improved mitochondrial function in peritoneal tissue, resulting in increased mitochondrial membrane potential and adenosine triphosphate production. This study suggests that CHP can significantly prevent PF in peritoneal dialysis patients by modulating HDAC3 expression and associated signaling pathways, reducing fibrosis and inflammation markers, and improving mitochondrial function.

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Section: Methodsmentioning

confidence: 99%

Protective effect of Cyclo(His‐Pro) on peritoneal fibrosis through regulation of HDAC3 expression

Kim,

Han,

Kim

et al. 2024

The FASEB Journal

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“…Moreover, a recent study has demonstrated that an octapeptide possessing anti-TGM properties had a beneficial impact on guinea pigs by mitigating lung inflammation. Additionally, a recent study reported that a TGM-2 inhibitor protected kidney cells from the accumulation of ECM molecules, apoptosis, and inflammatory responses [64]. Anti-muscarinic drugs were able to change collagen and other structural molecules in animal models of myopia, establishing a link to scleral connective tissue in these pathways.…”

Section: Transglutaminase As a Target For Drugsmentioning

confidence: 99%

Molecular Basis of Transglutaminase-2 and Muscarinic Cholinergic Receptors in Experimental Myopia: A Target for Myopia Treatment

Barathi

Tong

2023

Biomolecules

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Myopia, a prevalent refractive error disorder worldwide, is characterized by the elongation of the eye, leading to visual abnormalities. Understanding the genetic factors involved in myopia is crucial for developing therapeutic and preventive measures. Unfortunately, only a limited number of genes with well-defined functionality have been associated with myopia. In this study, we found that the homozygous TGM2-deleted gene in mice protected against the development of myopia by slowing down the elongation of the eye. The effectiveness of gene knockdown was confirmed by achieving a 60 percent reduction in TGM-2 transcript levels through the use of TGM-2-specific small interfering RNA (siRNA) in human scleral fibroblasts (SFs). Furthermore, treating normal mouse SFs with various transglutaminase inhibitors led to the down-regulation of TGM-2 expression, with the most significant reduction observed with specific TGM-2 inhibitors. Additionally, the study found that the pharmacological blockade of muscarinic receptors also slowed the progression of myopia in mice, and this effect was accompanied by a decrease in TGM-2 enzyme expression. Specifically, mice with homozygous mAChR5, mAChR1, and/or mAChR4 and knockout mice exhibited higher levels of TGM-2 mRNA compared to mice with homozygous mAChR2 and three knockout mice (fold changes of 5.8, 2.9, 2.4, −2.2, and −4.7, respectively; p < 0.05). These findings strongly suggest that both TGM-2 and muscarinic receptors play central roles in the development of myopia, and blocking these factors could potentially be useful in interfering with the progression of this condition. In conclusion, targeting TGM-2 may have a beneficial effect regarding myopia, and this may also be at least partially be the mechanism of anti-muscarinic drugs in myopia. Further studies should investigate the interaction between TGM-2 and muscarinic receptors, as well as the changes in other extracellular matrix genes associated with growth during the development of myopia.

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“…Indeed, this extracellular integrin/TG2/fibronectin binding is important in various disease conditions, such as cancer cell metastasis and glial scarring [105,106]. Moreover, increased extracellular TG2 plays a role in the aberrant transamidation of extracellular matrix components and fibrosis progression in the kidney [7], liver [107], and heart [108,109] in disease states.…”

Section: Extracellular Tg2mentioning

confidence: 99%

“…TG2 is ubiquitously expressed both inside and outside the cell and is involved in several cell biological phenomena, including cell proliferation, differentiation, and cell death [3]. In mammals, TG2 is distributed throughout the body, including the extracellular matrix and intracellular compartments of all tissues, and is implicated in several diseases, including celiac disease, cancer, fibrosis, and neurodegenerative diseases [4][5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Pathogenetic Contributions and Therapeutic Implications of Transglutaminase 2 in Neurodegenerative Diseases

Liu,

Mouradian

2024

IJMS

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Neurodegenerative diseases encompass a heterogeneous group of disorders that afflict millions of people worldwide. Characteristic protein aggregates are histopathological hallmark features of these disorders, including Amyloid β (Aβ)-containing plaques and tau-containing neurofibrillary tangles in Alzheimer’s disease, α-Synuclein (α-Syn)-containing Lewy bodies and Lewy neurites in Parkinson’s disease and dementia with Lewy bodies, and mutant huntingtin (mHTT) in nuclear inclusions in Huntington’s disease. These various aggregates are found in specific brain regions that are impacted by neurodegeneration and associated with clinical manifestations. Transglutaminase (TG2) (also known as tissue transglutaminase) is the most ubiquitously expressed member of the transglutaminase family with protein crosslinking activity. To date, Aβ, tau, α-Syn, and mHTT have been determined to be substrates of TG2, leading to their aggregation and implicating the involvement of TG2 in several pathophysiological events in neurodegenerative disorders. In this review, we summarize the biochemistry and physiologic functions of TG2 and describe recent advances in the pathogenetic role of TG2 in these diseases. We also review TG2 inhibitors tested in clinical trials and discuss recent TG2-targeting approaches, which offer new perspectives for the design of future highly potent and selective drugs with improved brain delivery as a disease-modifying treatment for neurodegenerative disorders.

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Inhibiting Transglutaminase 2 Mediates Kidney Fibrosis via Anti-Apoptosis

Cited by 7 publications

References 61 publications

Protective effect of Cyclo(His‐Pro) on peritoneal fibrosis through regulation of HDAC3 expression

Protective effect of Cyclo(His‐Pro) on peritoneal fibrosis through regulation of HDAC3 expression

Molecular Basis of Transglutaminase-2 and Muscarinic Cholinergic Receptors in Experimental Myopia: A Target for Myopia Treatment

Pathogenetic Contributions and Therapeutic Implications of Transglutaminase 2 in Neurodegenerative Diseases

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