VX-765 ameliorates inflammation and extracellular matrix accumulation by inhibiting the NOX1/ROS/NF-κB pathway in diabetic nephropathy.
J Pharm Pharmacol
; 74(3): 377-386, 2022 Mar 03.
Article
en En
| MEDLINE
| ID: mdl-34383065
ABSTRACT
OBJECTIVE:
This study explores the potential role of a highly selective caspase-1 inhibitor, VX-765, on extracellular matrix (ECM) accumulation and inflammation in diabetic nephropathy (DN) and the underlying mechanisms.METHODS:
DN rats, induced via high-fat diet/streptozotocin, were used to assess the effects of VX-765. Parallel experiments were carried out on rat mesangial cell line HBZY-1 exposed to high glucose (HG) to reveal the molecular mechanism of VX-765 in preventing DN. Survival analysis, biochemical parameters and renal oxidative stress of rats were observed, and Western blotting and immunofluorescence were evaluated. In vitro, Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX)1 silencing by RNA interference and quantitative real-time PCR (qPCR) assays were conducted in HBZY-1 cells exposed to HG levels. KEYFINDINGS:
In vivo, VX-765 significantly reduced the increase in urine albumin excretion and ECM accumulation. The phosphorylation of nuclear factor kappa-B (NF-κB) and the expression of pro-inflammatory cytokines IL-1ß, IL-6 and tumor necrosis factor (TNF)-α were significantly down-regulated. Furthermore, the generation of reactive oxygen species (ROS), phosphorylation of NF-κB and the expression of the NOX1 gene or protein were significantly decreased in HBZY-1 with VX-765 (5 µM) treatment in vitro.CONCLUSIONS:
Our results demonstrated that VX-765 exerts favourable effects on DN via the simultaneous alleviation of systemic metabolic syndrome and down-regulating the renal NOX1/ROS/NF-κB pathway, suggesting that it has therapeutic potential for DN.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Diabetes Mellitus Experimental
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Nefropatías Diabéticas
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Dipéptidos
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Para-Aminobenzoatos
/
Inflamación
Límite:
Animals
Idioma:
En
Revista:
J Pharm Pharmacol
Año:
2022
Tipo del documento:
Article
País de afiliación:
China