Cathepsin S–Dependent Protease–Activated Receptor-2 Activation: A New Mechanism of Endothelial Dysfunction

Nikolic-Paterson, David J.

doi:10.1681/asn.2015101162

Cited by 5 publications

(4 citation statements)

References 16 publications

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“…CTSS is an intriguing protein with functions linked to inflammation including regulation of major histocompatibility complex class II-mediated antigen presentation 6 , 7 . Furthermore, it also has important functions in extracellular matrix degradation 8 and activation of the protease activated receptor 2 9 which mediates inflammatory pain 10 , 11 , triggering cytokine production and itchiness 12 . Moreover, since CTSS exhibits potent activity at both acid and neutral pH levels 13 , elevated tear CTSS activity may alter tear composition, thereby affecting the ocular surface.…”

Section: Introductionmentioning

confidence: 99%

Increased Cathepsin S activity associated with decreased protease inhibitory capacity contributes to altered tear proteins in Sjögren’s Syndrome patients

Edman

Janga

Meng

et al. 2018

Sci Rep

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Cathepsin S (CTSS) activity is elevated in Sjögren’s Syndrome (SS) patient tears. Here we tested whether protease inhibition and cystatin C (Cys C) levels are reduced in SS tears, which could lead to enhanced CTSS-driven degradation of tear proteins. CTSS activity against Cys C, LF and sIgA was tested in SS or healthy control tears. Tears from 156 female subjects (33, SS; 33, rheumatoid arthritis; 31, other autoimmune diseases; 35, non-autoimmune dry eye (DE); 24, healthy controls) were analyzed for CTSS activity and Cys C, LF, and sIgA levels. Cys C and LF showed enhanced degradation in SS tears supplemented with recombinant CTSS, but not supplemented healthy control tears. CTSS activity was significantly increased, while Cys C, LF and sIgA levels were significantly decreased, in SS tears compared to other groups. While tear CTSS activity remained the strongest discriminator of SS in autoimmune populations, combining LF and CTSS improved discrimination of SS beyond CTSS in DE patients. Reductions in Cys C and other endogenous proteases may enhance CTSS activity in SS tears. Tear CTSS activity is reconfirmed as a putative biomarker of SS in an independent patient cohort while combined LF and CTSS measurements may distinguish SS from DE patients.

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Section: Introductionmentioning

confidence: 99%

Increased Cathepsin S activity associated with decreased protease inhibitory capacity contributes to altered tear proteins in Sjögren’s Syndrome patients

Edman

Janga

Meng

et al. 2018

Sci Rep

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“…Recent studies link activated PAR-2 to inflammatory processes associated with respiratory, gastrointestinal, metabolic, cardiovascular, and neurological diseases [ 28 ]. PAR-2 is expressed in a variety of cells such as keratinocytes [ 29 ], endothelial cells [ 30 ], fibroblasts [ 31 ], neurons [ 32 ], immune and inflammatory cells [ 33 ] and also in epithelial cells such as lung, gastrointestinal tract and corneal cells [ 34 , 35 , 36 ]. Recent studies have shown that CTSS can also cleave PAR-2 near the N-terminus at a site distinct from trypsin, exposing a novel tethered ligand and leading to the release of inflammatory mediators linked to several pathological conditions including hyperexcitability of nociceptive neurons promoting neurogenic inflammation and neuropathic pain [ 37 ], endothelial cell injury [ 38 , 39 ], visceral hyperalgesia during colitis [ 40 ], induction of chronic atopic dermatitis [ 41 ], and activation of liver tumor-initiating cells associated with hepatocellular carcinoma [ 42 ].…”

Section: Introductionmentioning

confidence: 99%

Cathepsin S Alters the Expression of Pro-Inflammatory Cytokines and MMP-9, Partially through Protease—Activated Receptor-2, in Human Corneal Epithelial Cells

Klinngam

Janga

et al. 2018

IJMS

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Cathepsin S (CTSS) activity is increased in tears of Sjögren’s syndrome (SS) patients. This elevated CTSS may contribute to ocular surface inflammation. Human corneal epithelial cells (HCE-T cells) were treated with recombinant human CTSS at activity comparable to that in SS patient tears for 2, 4, 8, and 24 h. Acute CTSS significantly increased HCE-T cell gene and protein expression of interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) from 2 to 4 h, while matrix metalloproteinase 9 (MMP-9), CTSS, and protease-activated receptor-2 (PAR-2) were increased by chronic CTSS (24 h). To investigate whether the increased pro-inflammatory cytokines and proteases were induced by CTSS activation of PAR-2, HCE-T cells were transfected with PAR-2 siRNA, reducing cellular PAR-2 by 45%. Cells with reduced PAR-2 expression showed significantly reduced release of IL-6, TNF-α, IL-1β, and MMP-9 into culture medium in response to acute CTSS, while IL-6, TNF-α, and MMP-9 were reduced in culture medium, and IL-6 and MMP-9 in cell lysates, after chronic CTSS. Moreover, cells with reduced PAR-2 expression showed reduced ability of chronic CTSS to induce gene expression of pro-inflammatory cytokines and proteases. CTSS activation of PAR-2 may represent a potential therapeutic target for amelioration of ocular surface inflammation in SS patients.

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“…Macrophage-derived CTSS mediates cell damage by activating PAR-2 located on endothelial cell surface. The application of the PAR-2 inhibitor (GB83) reduced endothelial cell injury and glomerulosclerosis, and this provided the first evidence for the pathogenic role of PAR-2 in DKD ( Nikolic-Paterson, 2016 ). More importantly, treatment of diabetic kidney disease in uninephrectomized db/db mice with a selective CTSS inhibitor (RO5461111) improved endothelial injury, albuminuria, and glomerulosclerosis as well as albumin leakage in the retina ( Kumar Vr et al, 2016 ).…”

Section: Discussionmentioning

confidence: 91%

Exploring the pathogenesis of diabetic kidney disease by microarray data analysis

et al. 2022

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Diabetic kidney disease (DKD) is a major complication of diabetes mellitus, and the leading contributor of end-stage renal disease. Hence, insights into the molecular pathogenesis of DKD are urgently needed. The purpose of this article is to reveal the molecular mechanisms underlying the pathogenesis of DKD. The microarray datasets of GSE30528 and GSE30529 were downloaded from the NCBI Gene Expression Omnibus (GEO) database to identify the common differentially expressed genes (DEGs) between the glomerular DKD (GDKD) and tubular DKD (TDKD), respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to analyze the function and pathways of the common DEGs. After constructing the protein–protein interaction (PPI) network and subnetwork analysis, three types of analyses were performed, namely, identification of hub genes, analysis of the coexpressed network, and exploration of transcription factors (TFs). Totally, 348 and 463 DEGs were identified in GDKD and TDKD, respectively. Then, 66 common DEGs (63 upregulated DEGs and three downregulated DEGs) were obtained in DKD patients. GO and KEGG pathway analyses revealed the importance of inflammation response, immune-related pathways, and extracellular matrix-related pathways, especially chemokines and cytokines, in DKD. Fifteen hub genes from the 66 common DEGs, namely, IL10RA, IRF8, LY86, C1QA, C1QB, CD53, CD1C, CTSS, CCR2, CD163, CCL5, CD48, RNASE6, CD52, and CD2 were identified. In summary, through the microarray data analysis, the common functions and hub genes greatly contribute to the elucidation of the molecular pathogenesis associated with DKD.

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Cathepsin S–Dependent Protease–Activated Receptor-2 Activation: A New Mechanism of Endothelial Dysfunction

Cited by 5 publications

References 16 publications

Increased Cathepsin S activity associated with decreased protease inhibitory capacity contributes to altered tear proteins in Sjögren’s Syndrome patients

Increased Cathepsin S activity associated with decreased protease inhibitory capacity contributes to altered tear proteins in Sjögren’s Syndrome patients

Cathepsin S Alters the Expression of Pro-Inflammatory Cytokines and MMP-9, Partially through Protease—Activated Receptor-2, in Human Corneal Epithelial Cells

Exploring the pathogenesis of diabetic kidney disease by microarray data analysis

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