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

Abstract

In the present study, we investigated the effects of xanthine oxidase (XO) inhibition on cholesterol-induced renal dysfunction in chronic kidney disease (CKD) mice, and in low-density lipoprotein (LDL)-treated human kidney proximal tubule epithelial (HK-2) cells. ApoE knockout (KO) mice underwent uninephrectomy to induce CKD, and were fed a normal diet or high-cholesterol (HC) diet along with the XO inhibitor topiroxostat (1 mg/kg/day). HK-2 cells were treated with LDL (200 µg/mL) and topiroxostat (5 µM) or small interfering RNA against xanthine dehydrogenase (siXDH; 20 nM). In uninephrectomized ApoE KO mice, the HC diet increased cholesterol accumulation, oxidative stress, XO activity, and kidney damage, while topiroxostat attenuated the hypercholesterolemia-associated renal dysfunction. The HC diet induced cholesterol accumulation by regulating the expressions of genes involved in cholesterol efflux (Nr1h3 and Abca1) and synthesis (Srebf2 and Hmgcr), which was reversed by topiroxostat. Topiroxostat suppressed the expressions of genes related to hypercholesterolemia-associated inflammation and fibrosis in the unilateral kidney. LDL stimulation evoked changes in the cholesterol metabolism, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and NF-κB pathways in HK-2 cells, which were mitigated by XO inhibition with topiroxostat or siXDH. These findings suggest that XO inhibition exerts renoprotective effects against hypercholesterolemia-associated kidney injury. XO could be a novel therapeutic target for hypercholesterolemia-associated kidney injury in uninephrectomized patients.

Uric Acid and Hypertension: Prognostic Role and Guide for Treatment

“…Since XOR is involved in intracellular UA production, the results of those genetic studies may underlie a critical role of intracellular UA production, instead of SUA, in the development and progression of hypertension. Supporting this hypothesis, plasma XO activity has been associated with CV outcomes, independently of SUA levels [ 98 , 99 ]. In addition, Boban et al showed that XOR was upregulated in subjects with essential hypertension [ 100 ].…”

Hyperuricemia and chronic kidney disease: to treat or not to treat

“…Intracellular levels might be higher in the setting where synthesis is stimulated, such as may be observed with high xanthine oxidoreductase (XO) activity. Plasma XO activity is associated with CKD progression and cardiovascular outcomes, independently of serum uric acid 45,46 . This could potentially explain why serum uric acid may not predict CKD by Mendelian randomization studies, as the polymorphisms in urate transporters Hyperuricemia is thought to cause kidney injury by both crystal-dependent and crystal-independent mechanisms 48 (Figure 1).…”

Kidney Inflammation, Injury and Regeneration 2020

“…In this current Special Edition, thirteen original research articles are presented: twelve in vivo studies in a murine or rat model and one in vitro study [ 3 ]. Seven studies show results from AKI models [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ], five from fibrosis models (or CKD models) [ 9 , 11 , 12 , 13 , 14 ] and two from a transplant rejection model [ 4 , 15 ] (two studies used two different in vivo models).…”

“…Others investigated the role of xanthine oxidase (XO) in CKD progression associated with hypercholesterolemia [ 13 ]. The authors used a murine model of uninephrectomy to induce CKD, in addition to a high-cholesterol diet with a XO inhibitor, and, also, evaluated the results in an in vitro model using immortal tubular epithelial cells.…”

“…The authors used a murine model of uninephrectomy to induce CKD, in addition to a high-cholesterol diet with a XO inhibitor, and, also, evaluated the results in an in vitro model using immortal tubular epithelial cells. The study clearly showed that XO inhibition exerts reno-protective effects and identifies XO as a novel therapeutic target for hypercholesterolemia-associated kidney injury [ 13 ]. Finally, one in vitro study using cisplatin-injured primary tubular epithelial cells focused on the decisive role of the Lipocalin-2 iron load for its pro-regenerative functions [ 3 ].…”