Table 2.

Regulatory mechanism of Nox4 in diabetic retinopathy.

Models	Intervention	Regulating factors/Signal pathways	Main results	Conclusion	Reference
The retina of db/db diabetic mice and high glucose-induced RCECs	Nox4 inhibition or lovastatin treatment	Nox4/VEGF	Nox4↓, NADPH oxidase activity↓, ROS↓, VEGF↓; Nox4-mediated VEGF overexpression led to diabetic retinal vascular permeability and neovascularization	Nox4 may promote angiogenesis in a VEGF-dependent manner.	[[89], [90], [91]]
STZ-induced diabetic mice endothelial cells	Knockdown of the ADAM17 gene	ADAM17	Nox4↓, oxidative stress↓	ADAM17 is an upstream regulator of Nox4 and could be a new therapeutic target for diabetic microangiopathy.	[92]
HRVECs	Knockdown of CCN1 (siRNA or CRISPR-Cas9)	CCN1	Nox4↓, ROS↓, oxidative stress↓	CCN1/Nox4 axis could be a potential approach for the treatment of DR.	[93]
High glucose-induced HRECs	γ-secretase inhibitor (GSI)	Notch	Notch activity↓, Nox4↓, ROS↓, apoptosis↓	Notch is a potential upstream regulator of Nox4.	[87]
LPS-activated microglia and pericyte culture systems	a Nox inhibitor (DPI)	Microglia activation	Nox4↓, UCP2↑, ROS↓, ΔΨm↑, NF-κB-p65↓, cleaved Caspase-3↓, inhibited pericyte oxidative damage and apoptosis	Activated microglia may promote pericyte apoptosis by enhancing ROS production.	[95]