ArticlePloS one2014
Tissue kallikrein mediates pro-inflammatory pathways and activation of protease-activated receptor-4 in proximal tubular epithelial cells.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers, 1 of them a synthesis that pooled it.
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Who cites it
26 citing papers in PubMed, 1 synthesis or guideline pooled it, 49 citations in OpenAlex.
- Characterization and Functions of Protease-Activated Receptor 2 in Obesity, Diabetes, and Metabolic Syndrome: A Systematic Review.BioMed research international · 2016Pooled it
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- Kallikrein-kinin system as a potential target for the treatment of intervertebral disc degeneration.European journal of medical research · 2025Review
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- Paneth cells inhibit intestinal stem cell proliferation through the bone morphogenic protein 7 pathway under rotavirus-mediated intestinal injury.World journal of gastroenterology · 2025Article
- Serine proteases and protease-activated receptors signaling in the kidney.American journal of physiology. Cell physiology · 2025Review
- A Novel Protocol for Culturing Polarized Proximal Tubular Epithelial Cells from Kidney Biopsies: Enhancing Platforms for Drug Excretion and Nephrotoxicity Studies.Journal of xenobiotics · 2025Article
- Gut microbial metabolites SCFAs and chronic kidney disease.Journal of translational medicine · 2024Review
- Role of protease-activated receptor 4 in mouse models of acute and chronic kidney injury.American journal of physiology. Renal physiology · 2024Article
- Integrative single-cell characterization of a frugivorous and an insectivorous bat kidney and pancreas.Nature communications · 2024Article
- Comprehensive analysis of molecular mechanisms underlying kidney stones: gene expression profiles and potential diagnostic markers.Frontiers in genetics · 2024Article
- Anti-inflammatory role of extracellular l-arginine through calcium sensing receptor in human renal proximal tubular epithelial (HK-2) cells.International immunopharmacology · 2023Article
- Analysis of IGHA1 and other salivary proteins post half marathon in female participants.PeerJ · 2023Article
- Short-Chain Fatty Acids in Chronic Kidney Disease: Focus on Inflammation and Oxidative Stress Regulation.International journal of molecular sciences · 2022Review
- Blocking Connexin-43 mediated hemichannel activity protects against early tubular injury in experimental chronic kidney disease.Cell communication and signaling : CCS · 2020Article
- Innate immunity in diabetic kidney disease.Nature reviews. Nephrology · 2020Review
- Associations of ACE I/D polymorphism with the levels of ACE, kallikrein, angiotensin II and interleukin-6 in STEMI patients.Scientific reports · 2019Article
- Pilot GWAS of caries in African-Americans shows genetic heterogeneity.BMC oral health · 2019Article
- Article
- Urinary peptidomics analysis reveals proteases involved in diabetic nephropathy.Scientific reports · 2017Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tissue kallikrein (KLK1) expression is up-regulated in human diabetic kidney tissue and induced by high glucose (HG) in human proximal tubular epithelial cells (PTEC). Since the kallikrein-kinin system (KKS) has been linked to cellular inflammatory process in many diseases, it is likely that KLK1 expression may mediate the inflammatory process during the development of diabetic nephropathy. In this study, we explored the role of KLK1 in tubular pro-inflammatory responses under the diabetic milieu. Recombinant KLK1 stimulated the production of inflammatory cytokines in PTEC via the activation of p42/44 and p38 MAPK signaling pathways. Molecular knockdown of endogenous KLK1 expression by siRNA transfection in PTEC attenuated advanced glycation end-products (AGE)-induced IL-8 and ICAM-1 productions in vitro. Interestingly, exposure of PTEC to KLK1 induced the expression of protease-activated receptors (PARs). There was a 2.9-fold increase in PAR-4, 1.4-fold increase in PAR-1 and 1.2-fold increase in PAR-2 mRNA levels. Activation of PAR-4 by a selective agonist was found to elicit the pro-inflammatory and pro-fibrotic phenotypes in PTEC while blockade of the receptor by specific antagonist attenuated high glucose-induced IL-6, CCL-2, CTGF and collagen IV expression. Calcium mobilization by the PAR-4 agonist in PTEC was desensitized by pretreatment with KLK1. Consistent with these in vitro findings, there was a markedly up-regulation of tubular PAR-4 expression in human diabetic renal cortical tissues. Together, these results suggest that up-regulation of KLK1 in tubular epithelial cells may mediate pro-inflammatory pathway and PAR activation during diabetic nephropathy and provide a new therapeutic target for further investigation.
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