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Genetic and Pharmacological Inhibition of NOX4 Protects Against Rhabdomyolysis-Induced Acute Kidney Injury Through
Zhuyun Zhang1, Jiameng Li2, Shanshan Chen3
1Department of Nephrology, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China.
Abstract:
Rhabdomyolysis is a severe condition that commonly leads to acute kidney injury (AKI), with limited targeted treatments for rhabdomyolysis-induced AKI (RIAKI) adding to the challenge. Emerging evidence implicates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) in the pathological processes of various kidney diseases, but its role in RIAKI remains unclear. We applied renal tubular epithelial cell (RTEC)-specific NOX4 knockout and the NOX4 inhibitor GKT137831 to treat RIAKI in vivo and in vitro. We found that genetic and pharmacological inhibition of NOX4 protected against glycerol-induced renal dysfunction, mitigated inflammatory responses and attenuated apoptotic rates. Additionally, NOX4 blockade suppressed the accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA), and enhanced the activities of antioxidant enzymes. Furthermore, NOX4 inhibition reduced the expression of endoplasmic reticulum stress (ERS)-associated proteins at both the RNA and protein levels. Collectively, these findings demonstrate that genetic and pharmacological suppression of NOX4 protects against RIAKI by reducing ROS generation, boosting antioxidant defense and inhibiting ERS activation. NOX4 inhibition may offer a potential approach for developing new treatment options for RIAKI.
Insights
Targeting nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) shows promise for treating rhabdomyolysis-induced acute kidney injury (RIAKI). Inhibiting NOX4 reduces kidney damage, inflammation, and cell death, offering a potential new therapeutic strategy.
Area of Science:
- Nephrology
- Molecular Biology
- Pathophysiology
Background:
- Rhabdomyolysis-induced acute kidney injury (RIAKI) presents a significant clinical challenge with limited targeted therapies.
- Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) is implicated in kidney disease, but its specific role in RIAKI is not well understood.
Purpose of the Study:
- To investigate the role of NOX4 in RIAKI.
- To evaluate the therapeutic potential of NOX4 inhibition in RIAKI.
Main Methods:
- Utilized renal tubular epithelial cell (RTEC)-specific NOX4 knockout models.
- Administered the NOX4 inhibitor GKT137831 in vivo and in vitro to treat glycerol-induced RIAKI.
- Assessed renal function, inflammatory markers, apoptosis, oxidative stress, and endoplasmic reticulum stress (ERS).
Main Results:
- Genetic and pharmacological NOX4 inhibition protected against renal dysfunction and reduced inflammation and apoptosis in RIAKI models.
- NOX4 blockade suppressed reactive oxygen species (ROS) and malondialdehyde (MDA) accumulation, while enhancing antioxidant enzyme activity.
- Inhibition of NOX4 decreased the expression of endoplasmic reticulum stress (ERS)-associated proteins.
Conclusions:
- NOX4 plays a critical role in the pathogenesis of RIAKI.
- Suppression of NOX4 mitigates RIAKI by reducing oxidative stress and inhibiting ERS activation.
- Targeting NOX4 represents a promising therapeutic strategy for RIAKI.
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