Table 1.

Regulatory mechanism of Nox4 in diabetic kidney disease.

Area of action	Regulating factors/Signal pathways	Main results	Reference
Kidney	Rho/Rho-kinase	Upregulated renal cortical Nox4 expression; increased urinary albumin, 8-OHdG excretion; Rho-kinase inhibitor (Fasudil) reversed the above effects.	[46,47]
	HIF-1	Upregulated Nox4 protein expression and NADPH-dependent ROS production; Resulted in total renal glomerular hypertrophy, mesangial matrix expansion, extracellular matrix accumulation and urinary albumin excretion. HIF-1 inhibitor (YC-1) could reverse the above phenomena.	[51]
	ChREBP	Upregulated the protein expression levels of TXNIP, Nox4, 8-OHdG, and HO-1. The knockdown of ChREBP improved kidney function and apoptosis.	[52]
	ADAM17	Upregulated Nox4 expression and NADPH oxidase activity; increased fibronectin expression and matrix protein accumulation. ADAM17 inhibitor (TMI-005) or transfected with ADAM17-siRNA suppressed Nox4 expression and oxidative stress-induced matrix protein accumulation.	[53]
Mesangial cells (MCs)	PKC	Increased gene expression levels of Nox4 and p22phox; induced renal hypertrophy, glomerular enlargement, and hyperfiltration; Lack of PKC-β can protect against diabetes-induced renal dysfunction, fibrosis, and renal oxidative damage.	[44,58]
	HuR	Upregulated Nox4 protein and gene expression, increased ROS production and fibrotic injury. HuR siRNAs inhibited the above results.	[59]
	TXNIP	Increased overall and mitochondrial ROS, Nox4 protein expression, and NAPDH oxidase activity. TXNIP-deficient showed no corresponding changes in the high glucose environment.	[60]
	FOXP1	FOXP1 overexpression prevented abnormal activation of Akt/mTOR signaling, significantly reduced Nox4 expression and ROS production, and resisted proliferation, oxidative stress and extracellular matrix accumulation.	[61]
	Cx32	Cx32 overexpression inhibited the expression of Smurf1 and promoted the degradation of Nox4; downregulated the expression of FN and ICAM-1 and normalized renal function and fibrosis.	[50,56]
	Nox4-ROS-PKC-TRPC6	Overexpression of TRPC6 reversed the contractile function impairment of high glucose-induced MCs.	[63]
podocyte	AMPK/mTOR	Downregulated AMPK, upregulated mTOR, increased Nox4, NADPH oxidase activity and podocyte apoptosis; inhibition of mTOR effectively reversed the above changes.	[70]
	Rictor/mTORC2	Upregulated Nox4 expression, increased podocyte shedding and apoptosis, GBM thickness and proteinuria production. Antisense oligonucleotides targeting Rictor inhibited mTORC2 and normalized the above variations.	[71]
	CYP4A	CYP4A inhibitor (HET0016) blocked the impact of high glucose on NADPH oxidase activity, Nox4 protein and gene expression, and podocyte apoptosis.	[1]
	Smad3/ezrin/PKA/Nox4	Increased levels of phosphorylated Smad3 and phosphorylated ezrin, decreased levels of phosphorylated PKA, accompanied by increased levels of Nox4 expression and apoptosis.	[66]
	TGF-β receptor-Smad2/3	Increased the expression of Nox4 and ROS production, abnormal activation of Caspase-3, podocyte apoptosis; knockdown of Smad2/3 blocked the above phenomena caused by TGF-β1.	[67]
	Nox4/PKGIα	The activation of Nox4-dependent PKGIα increased the permeability of podocytes, leading to proteinuria; small interfering RNAs of Nox4 and PKGIα reversed the above phenomena.	[72]
	Nox4/TRPC6	Increased Nox4-derived H2O2 production and calcium influx, activated TRPC6 channel, leading to podocyte damage; knockdown of Nox4 reversed the above results.	[73]
	Microvesicles (MVs)	Increased Nox4 expression and the number of MVs, stimulated podocyte microangiogenesis; Nox4 siRNA slowed down the formation of podocyte-derived MVs induced by high glucose.	[74]
Renal tubular epithelial cells	Egr1	Knockdown of Egr1 downregulated Nox4 and α-SMA expression, reduced ROS generation, and alleviated EMT.	[49]
	AMPK	AMPK activators attenuated the increase of Nox4 protein expression and ROS, restored the upregulation of mesenchymal marker protein (α-SMA) and downregulation of epithelial marker protein (E-cadherin) by high glucose, alleviated the renal tubular interstitial fibrosis.	[78]
	MALAT1-LIN28A-Nox4	Upregulated MALAT1, LIN28A, and Nox4 expression, increased the production of ROS and inflammatory factors, resulted in apoptosis; activated AMPK/mTOR signaling and enhanced Nox4 stability; knockdown of MALAT1, LIN28A or Nox4 reversed these phenomena.	[79]
	p38MAPK	Upregulated Nox4 and p22phox protein expression levels, increased p38MAPK phosphorylation, fibronectin, and TGF-β1/2; Nox1/4 inhibitor (GK-136901) inhibited the activation of p38MAPK phosphorylation and attenuated fibronectin and TGF-β expression.	[23]