Table 5.

Epigenetic regulation of Nox4 and diabetic microvascular complications.

Diabetes complications	Regulating factors/Signal pathways	Main results	Reference
Diabetic Kidney Disease	miR-25	Effective inhibition of miRNA-25 increased Nox4 gene and protein expression levels.	[129,130]
	Myo-Inositol Oxygenase	DNA hypomethylation and histone hyperacetylation of the MIOX promoter led to the overexpression of ROS and Nox4.	[131]
	miR-423-5p	miR-423-5p overexpression inhibited Nox4-dependent ROS production; enhanced cell viability; inhibited apoptosis, inflammatory response and cytoskeletal damage.	[132]
	miR-15b-5p	miR‐15b‐5p overexpression eliminated Nox4 overactivation, increased malondialdehyde content and decreased antioxidant enzyme activity induced by high glucose.	[133]
	miR146a	miR146a overexpression downregulated Nox4 protein level, ROS generation, oxidative stress, and inflammation; decreased VCAM-1 and ICAM-1 protein expression.	[134]
Diabetic Retinopathy	miR-590-3p	Inhibition of miR-590-3p upregulated NLRP1, Nox4/ROS/TXNIP/NLRP3 pathway and Caspase-1 protein expression. Conversely, overexpression of miR-590-3p could reverse the above effects.	[135]
	miR-99a-5p	As DR progressed, miR-99a-5p levels decreased and levels of Nox4, FPG, HOMA-IR and HbA1c increased in diabetic patients. In contrast, overexpression of miR-99a-5p mitigated the deleterious effects of HG.	[137]
Diabetic cardiomyopathy	miR-372-3p	miR-372-3p KD treatment raised expression of p-PI3K, p-AKT, p-mTOR, p-P70S6K and HIF-1α, while downregulating Nox2, and Nox4 expression. In addition, LVFS and LVEF were increased, LVIDd and LVIDs were decreased.	[138]
Diabetic neuropathy	miR-25	Decreased miR-25 levels, accompanied by increased Nox4 expression and ROS levels, as well as inhibition of PKC activation, reduced AGEs and RAGE levels.	[139]