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The Crucial Role of Xanthine Oxidase in CKD Progression Associated with Hypercholesterolemia
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 un...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589966/ https://www.ncbi.nlm.nih.gov/pubmed/33050202 http://dx.doi.org/10.3390/ijms21207444 |
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author | Kim, You-Jin Oh, Se-Hyun Ahn, Ji-Sun Yook, Ju-Min Kim, Chan-Duck Park, Sun-Hee Cho, Jang-Hee Kim, Yong-Lim |
author_facet | Kim, You-Jin Oh, Se-Hyun Ahn, Ji-Sun Yook, Ju-Min Kim, Chan-Duck Park, Sun-Hee Cho, Jang-Hee Kim, Yong-Lim |
author_sort | Kim, You-Jin |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7589966 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-75899662020-10-29 The Crucial Role of Xanthine Oxidase in CKD Progression Associated with Hypercholesterolemia Kim, You-Jin Oh, Se-Hyun Ahn, Ji-Sun Yook, Ju-Min Kim, Chan-Duck Park, Sun-Hee Cho, Jang-Hee Kim, Yong-Lim Int J Mol Sci Article 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. MDPI 2020-10-09 /pmc/articles/PMC7589966/ /pubmed/33050202 http://dx.doi.org/10.3390/ijms21207444 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Kim, You-Jin Oh, Se-Hyun Ahn, Ji-Sun Yook, Ju-Min Kim, Chan-Duck Park, Sun-Hee Cho, Jang-Hee Kim, Yong-Lim The Crucial Role of Xanthine Oxidase in CKD Progression Associated with Hypercholesterolemia |
title | The Crucial Role of Xanthine Oxidase in CKD Progression Associated with Hypercholesterolemia |
title_full | The Crucial Role of Xanthine Oxidase in CKD Progression Associated with Hypercholesterolemia |
title_fullStr | The Crucial Role of Xanthine Oxidase in CKD Progression Associated with Hypercholesterolemia |
title_full_unstemmed | The Crucial Role of Xanthine Oxidase in CKD Progression Associated with Hypercholesterolemia |
title_short | The Crucial Role of Xanthine Oxidase in CKD Progression Associated with Hypercholesterolemia |
title_sort | crucial role of xanthine oxidase in ckd progression associated with hypercholesterolemia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589966/ https://www.ncbi.nlm.nih.gov/pubmed/33050202 http://dx.doi.org/10.3390/ijms21207444 |
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