ArticleJournal of the American Society of Nephrology : JASN2016
Cathepsin S Cleavage of Protease-Activated Receptor-2 on Endothelial Cells Promotes Microvascular Diabetes Complications.
Article in Journal of the American Society of Nephrology : JASN, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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43 citing papers in PubMed, 76 citations in OpenAlex.
- ADAMTS13 ameliorates diabetic nephropathy by Nrf2/GPX4/eNOS signaling pathway.Renal failure · 2026Article
- Hyperglycemia-Induced Microglial CTSS Disrupts Blood-Retinal Barrier Integrity via PAR2-Dependent Downregulation of Endothelial MFSD2A.CNS neuroscience & therapeutics · 2026Article
- Functional characterization of podocyte-expressed THSD7A in experimental membranous nephropathy.JCI insight · 2026Article
- Integrative Proteome- and Phenome-Wide Assessment Uncovers Causal Protein Drivers and Drug Targets for Heterogeneous Kidney Diseases.medRxiv : the preprint server for health sciences · 2025Article
- The pH-Dependent Specificity of Cathepsin S and Its Implications for Inflammatory Communications and Disease.Biochemistry · 2025Article
- The Many Faces of Protease-Activated Receptor 2 in Kidney Injury.Biomedicines · 2025Review
- Multi-omics analysis reveals that low cathepsin S expression aggravates sepsis progression and worse prognosis via inducing monocyte polarization.Frontiers in cellular and infection microbiology · 2025Article
- Article
- Cathepsin S: molecular mechanisms in inflammatory and immunological processes.Frontiers in immunology · 2025Review
- Profiling of insulin-resistant kidney models and human biopsies reveals common and cell-type-specific mechanisms underpinning Diabetic Kidney Disease.Nature communications · 2024Article
- Identification of co-expressed central genes and transcription factors in acute myocardial infarction and diabetic nephropathy.BMC medical genomics · 2024Article
- Targeted deletion of von-Hippel-Lindau in the proximal tubule conditions the kidney against early diabetic kidney disease.Cell death & disease · 2023Article
- Identification of immune-related molecular clusters and diagnostic markers in chronic kidney disease based on cluster analysis.Frontiers in genetics · 2023Article
- Diagnostic value of serum cathepsin S in type 2 diabetic kidney disease.Frontiers in endocrinology · 2023Article
- Article
- Progressively Decreased HCN1 Channels Results in Cone Morphological Defects in Diabetic Retinopathy.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2022Article
- Role of cathepsin K in the expression of mechanical hypersensitivity following intra-plantar inflammation.Scientific reports · 2022Article
- The consequence of endothelial remodelling on the blood spinal cord barrier and nociception.Current research in physiology · 2022Review
- Lipopeptide Pepducins as Therapeutic Agents.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Exploring the pathogenesis of diabetic kidney disease by microarray data analysis.Frontiers in pharmacology · 2022Article
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24 authors at 7 institutions in 4 countries.
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Abstract
Endothelial dysfunction is a central pathomechanism in diabetes-associated complications. We hypothesized a pathogenic role in this dysfunction of cathepsin S (Cat-S), a cysteine protease that degrades elastic fibers and activates the protease-activated receptor-2 (PAR2) on endothelial cells. We found that injection of mice with recombinant Cat-S induced albuminuria and glomerular endothelial cell injury in a PAR2-dependent manner. In vivo microscopy confirmed a role for intrinsic Cat-S/PAR2 in ischemia-induced microvascular permeability. In vitro transcriptome analysis and experiments using siRNA or specific Cat-S and PAR2 antagonists revealed that Cat-S specifically impaired the integrity and barrier function of glomerular endothelial cells selectively through PAR2. In human and mouse type 2 diabetic nephropathy, only CD68(+) intrarenal monocytes expressed Cat-S mRNA, whereas Cat-S protein was present along endothelial cells and inside proximal tubular epithelial cells also. In contrast, the cysteine protease inhibitor cystatin C was expressed only in tubules. Delayed treatment of type 2 diabetic db/db mice with Cat-S or PAR2 inhibitors attenuated albuminuria and glomerulosclerosis (indicators of diabetic nephropathy) and attenuated albumin leakage into the retina and other structural markers of diabetic retinopathy. These data identify Cat-S as a monocyte/macrophage-derived circulating PAR2 agonist and mediator of endothelial dysfunction-related microvascular diabetes complications. Thus, Cat-S or PAR2 inhibition might be a novel strategy to prevent microvascular disease in diabetes and other diseases.
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