Nox4 as a novel therapeutic target for diabetic vascular complications

doi:10.1016/j.redox.2023.102781

Review

. 2023 Aug:64:102781.

doi: 10.1016/j.redox.2023.102781. Epub 2023 Jun 9.

Nox4 as a novel therapeutic target for diabetic vascular complications

Dongxia Wang¹, Jiaying Li², Gang Luo³, Juan Zhou³, Ning Wang³, Shanshan Wang³, Rui Zhao³, Xin Cao³, Yuxia Ma², Gang Liu⁴, Liping Hao⁵

Affiliations

¹ Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China; Department of Nutrition and Food Hygiene, School of Public Health, Hebei Medical University, Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, 050017, China.
² Department of Nutrition and Food Hygiene, School of Public Health, Hebei Medical University, Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, 050017, China.
³ Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China.
⁴ Department of Cardiology, The First Hospital of Hebei Medical University, Hebei International Joint Research Center for Structural Heart Disease, Hebei Key Laboratory of Cardiac Injury Repair Mechanism Study, Shijiazhuang, 050000, China. Electronic address: cardio2004@hebmu.edu.cn.
⁵ Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China. Electronic address: haolp@mails.tjmu.edu.cn.

PMID: 37321060
PMCID: PMC10363438
DOI: 10.1016/j.redox.2023.102781

Review

Nox4 as a novel therapeutic target for diabetic vascular complications

Dongxia Wang et al. Redox Biol. 2023 Aug.

. 2023 Aug:64:102781.

doi: 10.1016/j.redox.2023.102781. Epub 2023 Jun 9.

Authors

Dongxia Wang¹, Jiaying Li², Gang Luo³, Juan Zhou³, Ning Wang³, Shanshan Wang³, Rui Zhao³, Xin Cao³, Yuxia Ma², Gang Liu⁴, Liping Hao⁵

Affiliations

¹ Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China; Department of Nutrition and Food Hygiene, School of Public Health, Hebei Medical University, Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, 050017, China.
² Department of Nutrition and Food Hygiene, School of Public Health, Hebei Medical University, Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, 050017, China.
³ Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China.
⁴ Department of Cardiology, The First Hospital of Hebei Medical University, Hebei International Joint Research Center for Structural Heart Disease, Hebei Key Laboratory of Cardiac Injury Repair Mechanism Study, Shijiazhuang, 050000, China. Electronic address: cardio2004@hebmu.edu.cn.
⁵ Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China. Electronic address: haolp@mails.tjmu.edu.cn.

PMID: 37321060
PMCID: PMC10363438
DOI: 10.1016/j.redox.2023.102781

Abstract

Diabetic vascular complications can affect both microvascular and macrovascular. Diabetic microvascular complications, such as diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and diabetic cardiomyopathy, are believed to be caused by oxidative stress. The Nox family of NADPH oxidases is a significant source of reactive oxygen species and plays a crucial role in regulating redox signaling, particularly in response to high glucose and diabetes mellitus. This review aims to provide an overview of the current knowledge about the role of Nox4 and its regulatory mechanisms in diabetic microangiopathies. Especially, the latest novel advances in the upregulation of Nox4 that aggravate various cell types within diabetic kidney disease will be highlighted. Interestingly, this review also presents the mechanisms by which Nox4 regulates diabetic microangiopathy from novel perspectives such as epigenetics. Besides, we emphasize Nox4 as a therapeutic target for treating microvascular complications of diabetes and summarize drugs, inhibitors, and dietary components targeting Nox4 as important therapeutic measures in preventing and treating diabetic microangiopathy. Additionally, this review also sums up the evidence related to Nox4 and diabetic macroangiopathy.

Keywords: Diabetic vascular complications; Dietary strategies; Epigenetic regulation; Nox4; Nox4 inhibitors.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

**Fig. 1**
Upstream and downstream effectors of Nox4 involved in diabetic microvascular complications exposed to high glucose and diabetes. Abbreviations: HIF-1: hypoxia inducible factor-1; ChREBP: carbohydrate-responsive element-binding protein; PKC: protein kinase C; TXNIP: thioredoxin interacting protein; FOXP1: forkhead box prote1; Cx32: Connexin 32; TRPC6: transient receptor potential channel 6; AMPK: AMP-activated protein kinase; CYP4A: 4A family cytochrome P450; MIOX: Myo-Inositol Oxygenase; Egr1: early growth response 1; VEGF: vascular endothelial growth factor; Ang II: angiotensin II; TGF-β: transforming growth factor-β; LXR: liver X receptor.

**Fig. 2**
Nox4-dependent signaling pathways associated with diabetic kidney disease and their consequences, including renal fibrosis, inflammation, mesangial matrix expansion, apoptosis, ECM accumulation, proteinuria and impaired systolic function of MCs.

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References

1. Eid A.A., Gorin Y., Fagg B.M., et al. Mechanisms of podocyte injury in diabetes: role of cytochrome P450 and NADPH oxidases. Diabetes. 2009;58(5):1201–1211. - PMC - PubMed
1. Thum T., Fraccarollo D., Schultheiss M., et al. Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes. Diabetes. 2007;56(3):666–674. - PubMed
1. Shen G.X. Oxidative stress and diabetic cardiovascular disorders: roles of mitochondria and NADPH oxidase. Can. J. Physiol. Pharmacol. 2010;88(3):241–248. - PubMed
1. Lee S.R., An E.J., Kim J., et al. Function of NADPH oxidases in diabetic nephropathy and development of nox inhibitors. Biomol Ther (Seoul) 2020;28(1):25–33. - PMC - PubMed
1. Gorin Y., Block K., Hernandez J., et al. Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney. J. Biol. Chem. 2005;280(47):39616–39626. - PubMed

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[1] Eid A.A., Gorin Y., Fagg B.M., et al. Mechanisms of podocyte injury in diabetes: role of cytochrome P450 and NADPH oxidases. Diabetes. 2009;58(5):1201–1211. - PMC - PubMed

[2] Eid A.A., Gorin Y., Fagg B.M., et al. Mechanisms of podocyte injury in diabetes: role of cytochrome P450 and NADPH oxidases. Diabetes. 2009;58(5):1201–1211. - PMC - PubMed

[3] Thum T., Fraccarollo D., Schultheiss M., et al. Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes. Diabetes. 2007;56(3):666–674. - PubMed

[4] Thum T., Fraccarollo D., Schultheiss M., et al. Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes. Diabetes. 2007;56(3):666–674. - PubMed

[5] Shen G.X. Oxidative stress and diabetic cardiovascular disorders: roles of mitochondria and NADPH oxidase. Can. J. Physiol. Pharmacol. 2010;88(3):241–248. - PubMed

[6] Shen G.X. Oxidative stress and diabetic cardiovascular disorders: roles of mitochondria and NADPH oxidase. Can. J. Physiol. Pharmacol. 2010;88(3):241–248. - PubMed

[7] Lee S.R., An E.J., Kim J., et al. Function of NADPH oxidases in diabetic nephropathy and development of nox inhibitors. Biomol Ther (Seoul) 2020;28(1):25–33. - PMC - PubMed

[8] Lee S.R., An E.J., Kim J., et al. Function of NADPH oxidases in diabetic nephropathy and development of nox inhibitors. Biomol Ther (Seoul) 2020;28(1):25–33. - PMC - PubMed

[9] Gorin Y., Block K., Hernandez J., et al. Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney. J. Biol. Chem. 2005;280(47):39616–39626. - PubMed

[10] Gorin Y., Block K., Hernandez J., et al. Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney. J. Biol. Chem. 2005;280(47):39616–39626. - PubMed

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Nox4 as a novel therapeutic target for diabetic vascular complications

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Nox4 as a novel therapeutic target for diabetic vascular complications

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