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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 involved in the induction of renal fibrosis via the stabilization of ECM and the activation of TGF-?1. 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.

SUBMITTER: Tatsukawa H

PROVIDER: S-EPMC5943318 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Tatsukawa Hideki H Otsu Risa R Tani Yuji Y Wakita Ryosuke R Hitomi Kiyotaka K

Scientific reports 20180509 1

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 reduc ...[more]

PMID: 29743665

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Project description:Acute kidney injury (AKI) and chronic kidney disease (CKD) represent different stages of renal failure; thus, CKD can be regarded as a result of AKI deterioration. Previous studies have demonstrated that immune cell infiltration, oxidative stress, and metabolic mentalism can support renal fibrosis progression in AKI cases. However, the most important triggers and cell types involved in this pathological progression remain unclear. This study was conducted to shed light into the underlying cellular and molecular features of renal fibrosis progression through the analysis of three mouse whole kidney and one human single-cell RNA-sequencing datasets publicly available. According to the different causes of AKI (ischemia reperfusion injury [IRI] or cisplatin), the mouse samples were divided into the CIU [control-IRI-unilateral ureteral obstruction (UUO)] and CCU (control-cisplatin-UUO) groups. Comparisons between groups revealed eight different modules of differentially expressed genes (DEGs). A total of 1,214 genes showed the same expression pattern in both CIU and CCU groups; however, 1,816 and 1,308 genes were expressed specifically in the CCU and CIU groups, respectively. Further assessment of the DEGs according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway and Gene Ontology (GO) showed that T-cell activation, fatty acid metabolic process, and arachidonic acid metabolism were involved in the fibrosis progression in CIU and CCU. Single-cell RNA-sequencing data along with the collected DEGs information also revealed that the T-cell activation mainly happened in immune cells, whereas the fatty acid metabolic process and arachidonic acid metabolism occurred in tubule cells. Taken together, these findings suggest that the fibrosis process differed between the CIU and CCU stages, in which immune and tubule cells have different functions. These identified cellular and molecular features of the different stages of fibrosis progression may pave the way for exploring novel potential therapeutic strategies in the clinic.

Dataset Information

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

Publications

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

Similar Datasets

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