The Crucial Role of Xanthine Oxidase in CKD Progression Associated with Hypercholesterolemia

Area of Science:

• Nephrology
• Biochemistry
• Pharmacology

Background:

• Hypercholesterolemia is a significant risk factor for chronic kidney disease (CKD) progression.
• Cholesterol accumulation and oxidative stress contribute to renal dysfunction in CKD.
• Xanthine oxidase (XO) plays a role in oxidative stress and inflammation.

Purpose of the Study:

• To investigate the renoprotective effects of XO inhibition in cholesterol-induced kidney injury in CKD models.
• To explore the molecular mechanisms underlying XO's role in hypercholesterolemia-associated renal dysfunction.

Main Methods:

• ApoE knockout mice underwent uninephrectomy and were fed a high-cholesterol (HC) diet with or without the XO inhibitor topiroxostat.
• Human kidney proximal tubule epithelial (HK-2) cells were treated with low-density lipoprotein (LDL) and topiroxostat or small interfering RNA against xanthine dehydrogenase (siXDH).
• Gene expression, cholesterol metabolism, oxidative stress markers, and kidney damage were assessed.

Main Results:

• In CKD mice, the HC diet increased cholesterol, oxidative stress, and kidney damage, which topiroxostat attenuated.
• Topiroxostat reversed HC diet-induced alterations in genes regulating cholesterol efflux and synthesis.
• XO inhibition mitigated LDL-induced changes in cholesterol metabolism, NADPH oxidase, and NF-κB pathways in HK-2 cells.

Conclusions:

• Xanthine oxidase inhibition demonstrates renoprotective effects against hypercholesterolemia-associated kidney injury.
• XO inhibition normalizes cholesterol metabolism and reduces oxidative stress and inflammation in the kidney.
• XO represents a promising therapeutic target for managing kidney complications in hypercholesterolemia.