Dual blockade of protease-activated receptor 1 and 2 additively ameliorates diabetic kidney disease

Autor: Yamato Hashizume, Shu Yamakage, Shohei Mitsui, Hiroshi Sato, Akiyo Sekimoto, Emiko Sato, Yuji Oe, Satoshi Kumakura, Nobuyuki Takahashi, Sadayoshi Ito
Rok vydání: 2020
Předmět:
Collagen Type IV
0301 basic medicine
Agonist
Mice
129 Strain
Nitric Oxide Synthase Type III
Endothelium
Pyridines
Physiology
medicine.drug_class
medicine.medical_treatment
Inflammation
030204 cardiovascular system & hematology
Pharmacology
Kidney
Cell Line
Proinflammatory cytokine
Pathogenesis
03 medical and health sciences
0302 clinical medicine
medicine
Albuminuria
Animals
Humans
Receptor
PAR-2
Diabetic Nephropathies
Receptor
PAR-1
Receptor
Cell Proliferation
Mice
Knockout
business.industry
Endothelial Cells
Fibrosis
Mice
Inbred C57BL
Disease Models
Animal
Diabetes Mellitus
Type 1
030104 developmental biology
Cytokine
medicine.anatomical_structure
cardiovascular system
Cytokines
Drug Therapy
Combination
Imines
Inflammation Mediators
medicine.symptom
business
Oligopeptides
Research Article
Signal Transduction
Zdroj: Am J Physiol Renal Physiol
ISSN: 1522-1466
1931-857X
DOI: 10.1152/ajprenal.00595.2019
Popis: Protease-activated receptors (PARs) are coagulation protease targets, and they increase expression of inflammatory cytokines and chemokines in various diseases. Of all PARs, previous reports have shown that PAR1 or PAR2 inhibition is protective against diabetic glomerular injury. However, how PAR1 and PAR2 cooperatively contribute to diabetic kidney disease (DKD) pathogenesis and whether dual blockade of PARs is more effective in DKD remain elusive. To address this issue, male type I diabetic Akita mice heterozygous for endothelial nitric oxide synthase were used as a model of DKD. Mice (4 mo old) were divided into four treatment groups and administered vehicle, PAR1 antagonist (E5555, 60 mg·kg−1·day−1), PAR2 antagonist (FSLLRY, 3 mg·kg−1·day−1), or E5555 + FSLLRY for 4 wk. The results showed that the urinary albumin creatinine ratio was significantly reduced when both PAR1 and PAR2 were blocked with E5555 + FSLLRY compared with the vehicle-treated group. Dual blockade of PAR1 and PAR2 by E5555 + FSLLRY additively ameliorated histological injury, including mesangial expansion, glomerular macrophage infiltration, and collagen type IV deposition. Marked reduction of inflammation- and fibrosis-related gene expression in the kidney was also observed. In vitro, PAR1 and PAR2 agonists additively increased mRNA expression of macrophage chemoattractant protein 1 or plasminogen activator inhibitor-1 in human endothelial cells. Changes induced by the PAR1 agonist were blocked by a NF-κB inhibitor, whereas those of the PAR2 agonist were blocked by MAPK and/or NF-κB inhibitors. These findings suggest that PAR1 and PAR2 additively contribute to DKD pathogenesis and that dual blockade of both could be a novel therapeutic option for treatment of patients with DKD.
Databáze: OpenAIRE
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