Chymase released from mast cells produces pro-fibrotic, inflammatory, and vasoconstrictor agents. Studies were performed to test the hypothesis that chronic chymase inhibition provides a renal protective effect in type 2 diabetes. Diabetic (db/db) and control mice (db/m) were chronically infused with a chymase-specific inhibitor or vehicle for 8 weeks. Baseline urinary albumin excretion (UalbV) averaged 42 ± 3 and 442 ± 32 microg/d in control (n = 22) and diabetic mice (n = 27), respectively (p < .05). After administration of chymase inhibitor to diabetic mice, the change in UalbV was significantly lower (459 ± 57 microg/d) than in vehicle-treated diabetic mice (645 ± 108 microg/d). U V was not different at baseline between diabetic mice that would receive the chymase inhibitor (349 ± 56 ng/d, n = 6) and vehicle (373 ± 99 ng/d, n = 6) infusions, but increased significantly only in the vehicle-treated diabetic mice (p < .05). Glomeruli of diabetic kidneys treated chronically with chymase inhibition demonstrated reduced mesangial matrix expansion compared to glomeruli from untreated diabetic mice. Plasma angiotensin II levels were not altered by chymase inhibitor treatment. In summary, chronic chymase inhibition slowed the progression of urinary albumin excretion in diabetic mice. In conclusion, renal chymase may contribute to the progression of albuminuria in type 2 diabetes renal disease.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928241 | PMC |
| http://dx.doi.org/10.14814/phy2.14302 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Human intraepithelial mast cell differentiation and effector function are directed by TGF-β signaling.
J Clin Invest
January 2025
Jeff and Penny Vinik Center for Allergic Disease Research, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Mast cells (MCs) expressing a distinctive protease phenotype (MCTs) selectively expand within the epithelium of human mucosal tissues during type 2 (T2) inflammation. While MCTs are phenotypically distinct from subepithelial MCs (MCTCs), signals driving human MCT differentiation and this subset's contribution to inflammation remain unexplored. Here, we have identified TGF-β as a key driver of the MCT transcriptome in nasal polyps.
View Article and Find Full Text PDFAnalysis of kallikrein-related peptidase 7 (KLK7) autolysis reveals novel protease and cytokine substrates.
Biol Chem
December 2024
Departments of Biological Chemistry and Early Discovery Biochemistry, Genentech Inc., South San Francisco, CA, 94080, USA.
Kallikrein-related peptidase 7 (KLK7) is one of 15 members of the tissue kallikrein family and is primarily expressed in the skin epidermis. The activity of KLK7 is tightly regulated by multiple stages of maturation and reversible inhibition, similar to several other extracellular proteases. In this work, we used protease-specific inhibitors and active site variants to show that KLK7 undergoes autolysis at two separate sites in the 170 and 99 loops (chymotrypsinogen numbering), resulting in a loss of enzymatic activity.
View Article and Find Full Text PDFNeuronal substance P-driven MRGPRX2-dependent mast cell degranulation products differentially promote vascular permeability.
Front Immunol
December 2024
Department of Science of Allergy and Inflammation, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Mas-related G protein-coupled receptor b2 (Mrgprb2) binding to its cationic endogenous and exogenous ligands induces mast cell degranulation and promotes inflammation in mice. However, the physiological roles of its human homologue MRGPRX2 remain unclear. Here we aimed to elucidate the mechanisms by which MRGPRX2 regulates vascular permeability, and generated MRGPRX2 knock-in (MRGPRX2-KI) and Mrgprb2 knockout (Mrgprb2-KO) mice.
View Article and Find Full Text PDFIxochymostatin, a trypsin inhibitor-like (TIL) protein from Ixodes scapularis, inhibits chymase and impairs vascular permeability.
Int J Biol Macromol
January 2025
Tick-Pathogen Transmission Unit, Laboratory of Bacteriology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Hamilton, MT, USA. Electronic address:
Ticks obtain a blood meal by lacerating small blood vessels and ingesting the blood that flows to the feeding site, which triggers various host responses. However, ticks face the challenge of wound healing, a process involving hemostasis, inflammation, cell proliferation and migration, and remodeling, hindering blood acquisition. To overcome these obstacles, tick salivary glands produce an array of bioactive molecules.
View Article and Find Full Text PDFDiscovery and Preclinical Characterization of Fulacimstat (BAY 1142524), a Potent and Selective Chymase Inhibitor As a New Profibrinolytic Approach for Safe Thrombus Resolution.
J Med Chem
November 2024
Bayer AG, Pharmaceuticals, Research and Development, Aprather Weg 18a, 42113 Wuppertal, Germany.
Chymase is a serine-protease produced by mast cells. In the past few decades, its role in fibrotic diseases triggered the search for orally available chymase inhibitors. Aiming at reducing adverse cardiac remodeling after myocardial infarction, our research efforts resulted in the discovery of fulacimstat (BAY 1142524).
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!