Mechanism of Albuminuria Reduction by Chymase Inhibition in Diabetic Mice

Terai, Kentaro; Jin, Denan; Watase, Kenji; Imagawa, Akihisa

doi:10.3390/ijms21207495

Cited by 5 publications

(5 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Podocyte damage is relieved in db/db mice when podocytes are treated with a chymase inhibitor. These results suggest that podocyte injury in the glomerulus is caused by a chymase-dependent AngII-generating system ( 28 ). Regarding the regulation of chymase activity, SERPINA3 can inhibit several serine proteases secreted from neutrophils and mast cells, including chymase ( 31 ).…”

Section: Discussionmentioning

confidence: 95%

“…Chymase secreted by mast cells is involved in vasoactive peptide generation, extracellular matrix degradation, and glandular secretion regulation ( 28 , 29 ). Chymase is associated with diabetic renal tubular injury.…”

Section: Discussionmentioning

confidence: 99%

“…Through enzymatic reactions, chymase can activate stem cell factors. Activated stem cell factors can stimulate mast cell development and proliferation, resulting in an increased number of mast cells ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Immune-related SERPINA3 as a biomarker involved in diabetic nephropathy renal tubular injury

et al. 2022

View full text Add to dashboard Cite

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and has become a serious medical issue globally. Although it is known to be associated with glomerular injury, tubular injury has been found to participate in DN in recent years. However, mechanisms of diabetic renal tubular injury remain unclear. Here, we investigated the differentially expressed genes in the renal tubules of patients with DN by analyzing three RNA-seq datasets downloaded from the Gene Expression Omnibus database. Gene set enrichment analysis and weighted gene co-expression network analysis showed that DN is highly correlated with the immune system. The immune-related gene SERPINA3 was screened out with lasso regression and Kaplan–Meier survival analyses. Considering that SERPINA3 is an inhibitor of mast cell chymase, we examined the expression level of SERPINA3 and chymase in human renal tubular biopsies and found that SERPINA3 was upregulated in DN tubules, which is consistent with the results of the differential expression analysis. Besides, the infiltration and degranulation rates of mast cells are augmented in DN. By summarizing the biological function of SERPINA3, chymase, and mast cells in DN based on our results and those of previous studies, we speculated that SERPINA3 is a protective immune-related molecule that prevents renal tubular injury by inhibiting the proliferation and activation of mast cells and downregulating the activity of chymase.

show abstract

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Immune-related SERPINA3 as a biomarker involved in diabetic nephropathy renal tubular injury

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Disodium cromoglycate could inhibit the degranulation of mast cells and lighten tubulointerstitial collagen deposition in rats with type I diabetes ( 34 ). Chymase inhibitor TY-51469 suppressed oxidative stress in the renal podocytes of diabetic db/db mice, thereby decreasing albuminuria ( 35 ). This evidence revealed that mast cells were involved in DN progression.…”

Section: Discussionmentioning

confidence: 99%

GBP2 promotes M1 macrophage polarization by activating the notch1 signaling pathway in diabetic nephropathy

Liu

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

BackgroundDiabetic nephropathy (DN) is one of the most common diabetic complications, which has become the primary cause of end-stage renal disease (ESRD) globally. Macrophage infiltration has been proven vital in the occurrence and development of DN. This study was designed to investigate the hub genes involved in macrophage-mediated inflammation of DN via bioinformatics analysis and experimental validation.MethodsGene microarray datasets were obtained from the Gene Expression Omnibus (GEO) public website. Integrating the CIBERSORT, weighted gene co-expression network analysis (WGCNA) and DEGs, we screened macrophage M1-associated key genes with the highest intramodular connectivity. Subsequently, the Least Absolute Shrinkage and Selection Operator (LASSO) regression was utilized to further mine hub genes. GSE104954 acted as an external validation to predict the expression levels and diagnostic performance of these hub genes. The Nephroseq online platform was employed to evaluate the clinical implications of these hub genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to elucidate the dominant biological functions and signal pathways. Finally, we conducted experiments to verify the role of GBP2 in M1 macrophage-mediated inflammatory response and the underlying mechanism of this role.ResultsSixteen DEGs with the highest connectivity in M1 macrophages-associated module (paleturquoise module) were determined. Subsequently, we identified four hub genes through LASSO regression analysis, including CASP1, MS4A4A, CD53, and GBP2. Consistent with the training set, expression levels of these four hub genes manifested memorably elevated and the ROC curves indicated a good diagnostic accuracy with an area under the curve of greater than 0.8. Clinically, enhanced expression of these four hub genes predicted worse outcomes of DN patients. Given the known correlation between the first three hub genes and macrophage-mediated inflammation, experiments were performed to demonstrate the effect of GBP2, which proved that GBP2 contributed to M1 polarization of macrophages by activating the notch1 signaling pathway.ConclusionOur findings detected four hub genes, namely CASP1, MS4A4A, CD53, and GBP2, may involve in the progression of DN via pro-inflammatory M1 macrophage phenotype. GBP2 could be a promising prognostic biomarker and intervention target for DN by regulating M1 polarization.

show abstract

“…Mice were pretreated with consecutive intraperitoneal doses of 10 mg/kg TY‐51469, 11 , 29 according to the following scheme: 48 hours, 24 hours, and 30 minutes before IVC ligation. Animals were euthanized 24 hours after ligation.…”

Section: Methodsmentioning

confidence: 99%

Chymase Inhibition Resolves and Prevents Deep Vein Thrombosis Without Increasing Bleeding Time in the Mouse Model

Lapointe

Vincent

Giguère

et al. 2023

JAHA

Self Cite

View full text Add to dashboard Cite

Background Deep vein thrombosis (DVT) is the primary cause of pulmonary embolism and the third most life‐threatening cardiovascular disease in North America. Post‐DVT anticoagulants, such as warfarin, heparin, and direct oral anticoagulants, reduce the incidence of subsequent venous thrombi. However, all currently used anticoagulants affect bleeding time at various degrees, and there is therefore a need for improved therapeutic regimens in DVT. It has recently been shown that mast cells play a crucial role in a DVT murine model. The underlying mechanism involved in the prothrombotic properties of mast cells, however, has yet to be identified. Methods and Results C57BL/6 mice and mouse mast cell protease‐4 (mMCP‐4) genetically depleted mice (mMCP‐4 knockout) were used in 2 mouse models of DVT, partial ligation (stenosis) and ferric chloride–endothelial injury model of the inferior vena cava. Thrombus formation and impact of genetically repressed or pharmacologically (specific inhibitor TY‐51469) inhibited mMCP‐4 were evaluated by morphometric measurements of thrombi immunochemistry (mouse and human DVT), color Doppler ultrasound, bleeding times, and enzymatic activity assays ex vivo . Recombinant chymases, mMCP‐4 (mouse) and CMA‐1 (human), were used to characterize the interaction with murine and human plasmin, respectively, by mass spectrometry and enzymatic activity assays. Inhibiting mast cell–generated mMCP‐4, genetically or pharmacologically, resolves and prevents venous thrombus formation in both DVT models. Inferior vena cava blood flow obstruction was observed in the stenosis model after 6 hours of ligation, in control‐ but not in TY‐51469–treated mice. In addition, chymase inhibition had no impact on bleeding times of healthy or DVT mice. Furthermore, endogenous chymase limits plasmin activity in thrombi ex vivo. Recombinant mouse or human chymase degrades/inactivates purified plasmin in vitro. Finally, mast cell–containing immunoreactive chymase was identified in human DVT. Conclusions This study identified a major role for mMCP‐4, a granule‐localized protease of chymase type, in DVT formation. These findings support a novel pharmacological strategy to resolve or prevent DVT without affecting the coagulation cascade through the inhibition of chymase activity.

show abstract

Mechanism of Albuminuria Reduction by Chymase Inhibition in Diabetic Mice

Cited by 5 publications

References 46 publications

Immune-related SERPINA3 as a biomarker involved in diabetic nephropathy renal tubular injury

Immune-related SERPINA3 as a biomarker involved in diabetic nephropathy renal tubular injury

GBP2 promotes M1 macrophage polarization by activating the notch1 signaling pathway in diabetic nephropathy

Chymase Inhibition Resolves and Prevents Deep Vein Thrombosis Without Increasing Bleeding Time in the Mouse Model

Contact Info

Product

Resources

About