Isozyme-specific comprehensive characterization of transglutaminase-crosslinked substrates in kidney fibrosis

Abstract Chronic kidney disease is characterized by prolonged decline in renal function, excessive accumulation of ECM, and progressive tissue fibrosis. Transglutaminase (TG) is a crosslinking enzyme that catalyzes the formation of covalent bonds between glutamine and lysine residues, and is involve...

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Autores principales:	Hideki Tatsukawa, Risa Otsu, Yuji Tani, Ryosuke Wakita, Kiyotaka Hitomi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/66086460911a4f87a48181ed1f80a081
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spelling	oai:doaj.org-article:66086460911a4f87a48181ed1f80a0812021-12-02T16:08:03ZIsozyme-specific comprehensive characterization of transglutaminase-crosslinked substrates in kidney fibrosis10.1038/s41598-018-25674-42045-2322https://doaj.org/article/66086460911a4f87a48181ed1f80a0812018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25674-4https://doaj.org/toc/2045-2322Abstract Chronic kidney disease is characterized by prolonged decline in renal function, excessive accumulation of ECM, and progressive tissue fibrosis. Transglutaminase (TG) is a crosslinking enzyme that catalyzes the formation of covalent bonds between glutamine and lysine residues, and is involved in the induction of renal fibrosis via the stabilization of ECM and the activation of TGF-β1. Despite the accumulating evidences indicating that TG2 is a key enzyme in fibrosis, genetic knockout of TG2 reduced by only 50% the elevated protein crosslinking and fibrous protein in renal fibrosis model, whereas treatment with TG inhibitor almost completely reduced these levels. Here, we also clarified the distributions of TG isozymes and their in situ activities and identified the isozyme-specific crosslinked substrates for both TG1 and TG2 in fibrotic kidney. We found that TG1 activity was markedly enhanced in renal tubular epithelium and interstitial areas, whereas TG2 activity increased only in the extracellular space. In total, 47 and 67 possible candidates were identified as TG1 and TG2 substrates, respectively, only in fibrotic kidney. Among them, several possible substrates related to renal disease and fibrosis were identified. These findings provide novel insights into the mechanisms of renal fibrosis through the targeting of isozyme-specific TG substrates.Hideki TatsukawaRisa OtsuYuji TaniRyosuke WakitaKiyotaka HitomiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-18 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hideki Tatsukawa Risa Otsu Yuji Tani Ryosuke Wakita Kiyotaka Hitomi Isozyme-specific comprehensive characterization of transglutaminase-crosslinked substrates in kidney fibrosis
description	Abstract Chronic kidney disease is characterized by prolonged decline in renal function, excessive accumulation of ECM, and progressive tissue fibrosis. Transglutaminase (TG) is a crosslinking enzyme that catalyzes the formation of covalent bonds between glutamine and lysine residues, and is involved in the induction of renal fibrosis via the stabilization of ECM and the activation of TGF-β1. Despite the accumulating evidences indicating that TG2 is a key enzyme in fibrosis, genetic knockout of TG2 reduced by only 50% the elevated protein crosslinking and fibrous protein in renal fibrosis model, whereas treatment with TG inhibitor almost completely reduced these levels. Here, we also clarified the distributions of TG isozymes and their in situ activities and identified the isozyme-specific crosslinked substrates for both TG1 and TG2 in fibrotic kidney. We found that TG1 activity was markedly enhanced in renal tubular epithelium and interstitial areas, whereas TG2 activity increased only in the extracellular space. In total, 47 and 67 possible candidates were identified as TG1 and TG2 substrates, respectively, only in fibrotic kidney. Among them, several possible substrates related to renal disease and fibrosis were identified. These findings provide novel insights into the mechanisms of renal fibrosis through the targeting of isozyme-specific TG substrates.
format	article
author	Hideki Tatsukawa Risa Otsu Yuji Tani Ryosuke Wakita Kiyotaka Hitomi
author_facet	Hideki Tatsukawa Risa Otsu Yuji Tani Ryosuke Wakita Kiyotaka Hitomi
author_sort	Hideki Tatsukawa
title	Isozyme-specific comprehensive characterization of transglutaminase-crosslinked substrates in kidney fibrosis
title_short	Isozyme-specific comprehensive characterization of transglutaminase-crosslinked substrates in kidney fibrosis
title_full	Isozyme-specific comprehensive characterization of transglutaminase-crosslinked substrates in kidney fibrosis
title_fullStr	Isozyme-specific comprehensive characterization of transglutaminase-crosslinked substrates in kidney fibrosis
title_full_unstemmed	Isozyme-specific comprehensive characterization of transglutaminase-crosslinked substrates in kidney fibrosis
title_sort	isozyme-specific comprehensive characterization of transglutaminase-crosslinked substrates in kidney fibrosis
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/66086460911a4f87a48181ed1f80a081
work_keys_str_mv	AT hidekitatsukawa isozymespecificcomprehensivecharacterizationoftransglutaminasecrosslinkedsubstratesinkidneyfibrosis AT risaotsu isozymespecificcomprehensivecharacterizationoftransglutaminasecrosslinkedsubstratesinkidneyfibrosis AT yujitani isozymespecificcomprehensivecharacterizationoftransglutaminasecrosslinkedsubstratesinkidneyfibrosis AT ryosukewakita isozymespecificcomprehensivecharacterizationoftransglutaminasecrosslinkedsubstratesinkidneyfibrosis AT kiyotakahitomi isozymespecificcomprehensivecharacterizationoftransglutaminasecrosslinkedsubstratesinkidneyfibrosis
_version_	1718384660623392768

Isozyme-specific comprehensive characterization of transglutaminase-crosslinked substrates in kidney fibrosis

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