Transglutaminase 2 as a novel target in chronic kidney disease - Methods, mechanisms and pharmacological inhibition

التفاصيل البيبلوغرافية
العنوان: Transglutaminase 2 as a novel target in chronic kidney disease - Methods, mechanisms and pharmacological inhibition
المؤلفون: Judit Prat-Duran, Niels H. Buus, Estéfano Pinilla, Rikke Nørregaard, Ulf Simonsen
المصدر: Prat-Duran, J, Pinilla, E, Nørregaard, R, Simonsen, U & Buus, N H 2021, ' Transglutaminase 2 as a novel target in chronic kidney disease-Methods, mechanisms and pharmacological inhibition ', Pharmacology & Therapeutics, vol. 222, 107787 . https://doi.org/10.1016/j.pharmthera.2020.107787
سنة النشر: 2020
مصطلحات موضوعية: 0301 basic medicine, Angiotensin receptor, Tissue transglutaminase, Pharmacology, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, Chronic allograft nephropathy, Chronic kidney disease, Renal fibrosis, Extracellular, Medicine, Pharmacological inhibition, Animals, Humans, Pharmacology (medical), Protein Glutamine gamma Glutamyltransferase 2, Renal Insufficiency, Chronic, biology, business.industry, Diabetes, medicine.disease, Transglutaminase 2, 030104 developmental biology, Genetic inhibition, 030220 oncology & carcinogenesis, biology.protein, business, Transforming growth factor, Kidney disease
الوصف: Chronic kidney disease (CKD) is a global health problem with a prevalence of 10-15%. Progressive fibrosis of the renal tissue is a main feature of CKD, but current treatment strategies are relatively unspecific and delay, but do not prevent, CKD. Exploration of novel pharmacological targets to inhibit fibrosis development are therefore important. Transglutaminase 2 (TG2) is known to be central for extracellular collagenous matrix formation, but TG2 is a multifunctional enzyme and novel research has broadened our view on its extra- and intracellular actions. TG2 exists in two conformational states with different catalytic properties as determined by substrate availability and local calcium concentrations. The open conformation of TG2 depends on calcium and has transamidase activity, central for protein modification and cross-linking of extracellular protein components, while the closed conformation is a GTPase involved in transmembrane signaling processes. We first describe different methodologies to assess TG2 activity in renal tissue and cell cultures such as biotin cadaverine incorporation. Then we systematically review animal CKD models and preliminary studies in humans (with diabetic, IgA- and chronic allograft nephropathy) to reveal the role of TG2 in renal fibrosis. Mechanisms behind TG2 activation, TG2 externalization dependent on Syndecan-4 and interactions between TG and profibrotic molecules including transforming growth factor β and the angiotensin II receptor are discussed. Pharmacological TG2 inhibition shows antifibrotic effects in CKD. However, the translation of TG2 inhibition to treat CKD in patients is a challenge as clinical information is limited, and further studies on pharmacokinetics and efficacy of the individual compounds are required.
تدمد: 1879-016X
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4fe6c8c7708684ce5e2e1e0f56532ec0
https://pubmed.ncbi.nlm.nih.gov/33307141
حقوق: RESTRICTED
رقم الأكسشن: edsair.doi.dedup.....4fe6c8c7708684ce5e2e1e0f56532ec0
قاعدة البيانات: OpenAIRE