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VX-765 ameliorates inflammation and extracellular matrix accumulation by inhibiting the NOX1/ROS/NF-κB pathway in
Xiaokang Wang1, Tiesong Wu1, Hongyan Ma1
1Department of Pharmacy, Shenzhen Longhua District Central Hospital, The Affiliated Central Hospital of Shenzhen Longhua District, Guangdong Medical University, Shenzhen, China.
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.
Key Findings:
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-1β, 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.
Insights
VX-765, a caspase-1 inhibitor, effectively reduced inflammation and extracellular matrix buildup in diabetic nephropathy. It targets the NOX1/ROS/NF-κB pathway, showing therapeutic potential for this condition.
Area of Science:
- Nephrology
- Pharmacology
- Molecular Biology
Background:
- Diabetic nephropathy (DN) is a major complication of diabetes, characterized by extracellular matrix (ECM) accumulation and inflammation.
- The caspase-1 pathway and oxidative stress are implicated in the pathogenesis of DN.
- Novel therapeutic strategies targeting these pathways are needed.
Purpose of the Study:
- To investigate the therapeutic potential of VX-765, a selective caspase-1 inhibitor, in a rat model of diabetic nephropathy (DN).
- To elucidate the underlying mechanisms by which VX-765 affects ECM accumulation, inflammation, and oxidative stress in DN.
- To examine the role of the NOX1/ROS/NF-κB pathway in VX-765's protective effects.
Main Methods:
- Diabetic nephropathy was induced in rats using a high-fat diet and streptozotocin.
- VX-765 treatment effects were assessed on renal function, ECM accumulation, and inflammatory markers.
- In vitro studies on rat mesangial cells (HBZY-1) exposed to high glucose (HG) investigated molecular mechanisms, including NOX1 silencing and NF-κB activation.
Main Results:
- VX-765 significantly reduced albuminuria and ECM accumulation in DN rats.
- Treatment with VX-765 led to down-regulation of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and NF-κB phosphorylation.
- In vitro, VX-765 decreased reactive oxygen species (ROS) generation and NOX1 expression in HG-treated mesangial cells.
Conclusions:
- VX-765 demonstrates significant renoprotective effects in diabetic nephropathy.
- The drug alleviates systemic metabolic abnormalities and reduces renal inflammation and oxidative stress.
- VX-765's therapeutic potential for DN is linked to its ability to down-regulate the NOX1/ROS/NF-κB pathway.
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