NADPH-oxidase 4 protects against kidney fibrosis during chronic renal injury

Area of Science:

• Nephrology
• Molecular Biology
• Cell Biology

Background:

• NADPH oxidases (NOX) generate reactive oxygen species implicated in fibrosis.
• NOX4 is the primary renal NADPH oxidase, but its role in kidney disease is unclear.
• NOX2 also contributes to renal function.

Purpose of the Study:

• To investigate the roles of NOX4 and NOX2 in kidney fibrosis using a mouse model of unilateral urinary obstruction.
• To determine the specific contributions of NOX4 and NOX2 to chronic kidney injury.

Main Methods:

• Utilized wild-type, NOX4-deficient, NOX2-deficient, and NOX4/NOX2-deficient mice in a unilateral urinary obstruction model.
• Assessed interstitial fibrosis, tubular apoptosis, capillary density, and expression of key proteins (hypoxia-inducible factor-1α, vascular endothelial growth factor, NRF2).
• Employed NOX4 silencing in a mouse collecting duct cell line (mCCD(cl1)) to study cellular responses to TGF-β1 and hypoxia.

Main Results:

• NOX4-deficient mice showed increased interstitial fibrosis, tubular apoptosis, and oxidative stress post-obstruction.
• Absence of NOX4 led to reduced interstitial capillary density and lower expression of hypoxia-inducible factor-1α and vascular endothelial growth factor.
• NOX4 deficiency decreased NRF2 protein levels; NOX2 deficiency did not alter the NOX4-deficient phenotype.
• In vitro, NOX4 silencing exacerbated TGF-β1-induced apoptosis and impaired cellular responses to hypoxia.

Conclusions:

• NOX4 deficiency exacerbates kidney fibrosis, tubular cell apoptosis, and oxidative stress, independent of NOX2.
• NOX4 plays a critical role in maintaining kidney tubular cell survival and vascularization during injury.
• Targeting NOX4 may offer therapeutic potential for kidney diseases characterized by fibrosis.