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Independent of Renox, NOX5 Promotes Renal Inflammation and Fibrosis in Diabetes by Activating ROS-Sensitive Pathways
Jay C Jha1, Aozhi Dai1, Jessica Garzarella1
1Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
Abstract:
Excessive production of renal reactive oxygen species (ROS) plays a major role in diabetic kidney disease (DKD). Here, we provide key findings demonstrating the predominant pathological role of the pro-oxidant enzyme NADPH oxidase 5 (NOX5) in DKD, independent of the previously characterized NOX4 pathway. In patients with diabetes, we found increased expression of renal NOX5 in association with enhanced ROS formation and upregulation of ROS-sensitive factors early growth response 1 (EGR-1), protein kinase C-α (PKC-α), and a key metabolic gene involved in redox balance, thioredoxin-interacting protein (TXNIP). In preclinical models of DKD, overexpression of NOX5 in Nox4-deficient mice enhances kidney damage by increasing albuminuria and augmenting renal fibrosis and inflammation via enhanced ROS formation and the modulation of EGR1, TXNIP, ERK1/2, PKC-α, and PKC-ε. In addition, the only first-in-class NOX inhibitor, GKT137831, appears to be ineffective in the presence of NOX5 expression in diabetes. In vitro, silencing of NOX5 in human mesangial cells attenuated upregulation of EGR1, PKC-α, and TXNIP induced by high glucose levels, as well as markers of inflammation (TLR4 and MCP-1) and fibrosis (CTGF and collagens I and III) via reduction in ROS formation. Collectively, these findings identify NOX5 as a superior target in human DKD compared with other NOX isoforms such as NOX4, which may have been overinterpreted in previous rodent studies.
Insights
Diabetic kidney disease (DKD) involves excessive reactive oxygen species (ROS). This study highlights NADPH oxidase 5 (NOX5) as a key driver of DKD, offering a new therapeutic target beyond NOX4.
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Diabetic kidney disease (DKD) is characterized by excessive renal reactive oxygen species (ROS) production.
- NADPH oxidase 4 (NOX4) has been implicated, but its role may be overestimated.
- The specific contribution of other NOX isoforms in DKD pathogenesis requires further elucidation.
Purpose of the Study:
- To investigate the role of NADPH oxidase 5 (NOX5) in the development and progression of diabetic kidney disease (DKD).
- To compare the pathological significance of NOX5 with NOX4 in DKD.
- To evaluate NOX5 as a potential therapeutic target for DKD.
Main Methods:
- Analysis of renal NOX5 expression, ROS formation, and related factors in diabetic patients and preclinical DKD models.
- Utilizing Nox4-deficient mice with NOX5 overexpression to assess kidney damage.
- In vitro studies involving silencing NOX5 in human mesangial cells under high glucose conditions.
- Assessing the efficacy of a NOX inhibitor (GKT137831) in the presence of NOX5.
Main Results:
- Increased renal NOX5 expression, ROS production, and upregulation of EGR-1, PKC-α, and TXNIP were observed in diabetic patients.
- NOX5 overexpression in Nox4-deficient mice exacerbated DKD, increasing albuminuria, fibrosis, and inflammation.
- NOX5 silencing in vitro reduced high glucose-induced upregulation of inflammatory and fibrotic markers via decreased ROS.
- The NOX inhibitor GKT137831 was ineffective when NOX5 was expressed.
Conclusions:
- NADPH oxidase 5 (NOX5) plays a predominant pathological role in diabetic kidney disease (DKD), independent of NOX4.
- NOX5 is a more significant therapeutic target in human DKD than previously thought.
- Targeting NOX5 offers a promising strategy for managing diabetic kidney disease.
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