Uric acid increases fibronectin synthesis through upregulation of lysyl oxidase expression in rat renal tubular epithelial cells.
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.
Yang
Zhou
Z
Center of Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, China.
Xiaohua
Wang
W
Lei
Jiang
J
Ruoyun
Tan
T
Mingxia
Xiong
X
Weichun
He
H
Li
Fang
F
Ping
Wen
W
Junwei
Yang
Y
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism*; D005355:Fibrosis; D005455:Fluorescent Antibody Technique; D033461:Hyperuricemia / Q000201:enzymology* / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011339:Probenecid / Q000494:pharmacology; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D013997:Time Factors; D015854:Up-Regulation; D014527:Uric Acid / Q000097:blood / Q000378:metabolism*
D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D016328:NF-kappa B; D027361:Organic Anion Transporters; C103862:urate transporter; C077112:Lox protein, mouse; D014527:Uric Acid; D008249:Protein-Lysine 6-Oxidase; D011339:Probenecid