Document Detail


Uric acid increases fibronectin synthesis through upregulation of lysyl oxidase expression in rat renal tubular epithelial cells.
MedLine Citation:
PMID:  20484295     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Urate is produced as the major end product of purine metabolism. In the last decade, the incidence of hyperuricemia increased markedly, and similar trends in the epidemiology of metabolic syndrome have been observed. Hyperuricemia is associated with renal disease, and recent studies have reported that mild hyperuricemia results in hypertension, intrarenal vascular disease, and renal injury. This has led to the hypothesis that uric acid may contribute to renal fibrosis and progressive renal disease. Our purpose was to investigate the relationship between uric acid and renal tubular injury. We applied the method of intraperitoneal injection of uric acid to generate the hyperuricemic mouse model. Compared with the saline injection group, the expression of lysyl oxidase (LOX) and fibronectin in kidneys was increased significantly in hyperuricemic groups. In vitro, uric acid significantly induced NRK-52E cells to express the ECM marker fibronectin, as well as LOX, which plays a pivotal role in ECM maturation, in a time- and dose-dependent manner. Upregulation of the urate transporter URAT1, which is located in the apical membrane of proximal tubules, sensitized the uric acid-induced fibronectin and LOX induction, while both knocking down URAT1 expression in tubular epithelial cells by RNA interference and inhibiting URAT1 function pharmacologically attenuated LOX and fibronectin expression. Furthermore, knockdown of LOX expression by a small interfering RNA strategy led to a decrease in fibronectin abundance induced by uric acid treatment. In addition, evidence of a uric acid-induced activation of the NF-kappaB signaling cascade was observed. Our findings highlight a need for carefully reevaluating our previous view on the pathological roles of hyperuricemia in the kidney and nephropathy induced by uric acid in clinical practice.
Authors:
Zhou Yang; Wang Xiaohua; Jiang Lei; Tan Ruoyun; Xiong Mingxia; He Weichun; Fang Li; Wen Ping; Yang Junwei
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-05-19
Journal Detail:
Title:  American journal of physiology. Renal physiology     Volume:  299     ISSN:  1522-1466     ISO Abbreviation:  Am. J. Physiol. Renal Physiol.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-08-04     Completed Date:  2010-09-03     Revised Date:  2011-04-28    
Medline Journal Info:
Nlm Unique ID:  100901990     Medline TA:  Am J Physiol Renal Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  F336-46     Citation Subset:  IM    
Affiliation:
Center of Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, China.
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MeSH Terms
Descriptor/Qualifier:
Animals
Blotting, Western
Cell Line
Disease Models, Animal
Epithelial Cells / drug effects,  enzymology*,  pathology
Extracellular Matrix Proteins / metabolism
Fibronectins / metabolism*
Fibrosis
Fluorescent Antibody Technique
Hyperuricemia / enzymology*,  pathology
Kidney Tubules / drug effects,  enzymology*,  pathology
Male
Mice
Mice, Inbred C57BL
NF-kappa B / metabolism
Organic Anion Transporters / antagonists & inhibitors,  genetics,  metabolism
Probenecid / pharmacology
Protein-Lysine 6-Oxidase / genetics,  metabolism*
RNA Interference
Rats
Time Factors
Up-Regulation
Uric Acid / blood,  metabolism*
Chemical
Reg. No./Substance:
0/Extracellular Matrix Proteins; 0/Fibronectins; 0/NF-kappa B; 0/Organic Anion Transporters; 0/urate transporter; 149137-54-2/Lox protein, mouse; 57-66-9/Probenecid; 69-93-2/Uric Acid; EC 1.4.3.13/Protein-Lysine 6-Oxidase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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