Fucoidan from Laminaria japonica Inhibits Expression of GLUT9 and URAT1 via PI3K/Akt, JNK and NF-κB Pathways in Uric Acid-Exposed HK-2 Cells.

Yu Zhang,Xiaohui Tan,Fangping Li,Zhen Lin,Jianghua Shang,Chunyan Yang,Haiying Zheng,Huazhong Liu,Lingyu Li

doi:10.3390/md19050238

Abstract

This work aimed to investigate the effect of fucoidan (FPS) on urate transporters induced by uric acid (UA). The results showed that UA stimulated the expression of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1) in HK-2 cells, and FPS could reverse the effect. Moreover, UA could activate NF-κB, JNK and PI3K/Akt pathways, but both pathway inhibitors and FPS inhibited the UA-induced activation of these three pathways. These data suggested that FPS effectively inhibited the expression induction of reabsorption transporters URAT1 and GLUT9 by UA, through repressing the activation of NF-κB, JNK and PI3K/Akt signal pathways in HK-2 cells. The in vitro research findings support the in vivo results that FPS reduces serum uric acid content in hyperuricemia mice and rats through inhibiting the expression of URAT1 and GLUT9 in renal tubular epithelial cells. This study provides a theoretical basis for the application of FPS in the treatment of hyperuricemia.

Highlights

IntroductionHyperuricemia is considered a metabolic disease that induces gout, chronic nephrosis and insulin resistance
At a dose of 200 μg/mL, uric acid (UA) markedly increased the expression of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1) proteins (p < 0.01), and the protein contents were positively associated with UA dosage
It was found that a low dosage of UA failed to modify the expression level of transporter URAT1 (100 μg/mL, p > 0.05) and GLUT9 (50 μg/mL, p > 0.05), which suggests that urate at a low concentration may not affect the renal function of urate excretion, but a high concentration does

Summary

Introduction

Hyperuricemia is considered a metabolic disease that induces gout, chronic nephrosis and insulin resistance. Hyperuricemia accelerates vasculopathy and the occurrence and development of abnormal glucose tolerance, and is closely related to hypertension, atherosis, coronary heart disease, lipid metabolism disorder, obesity and sexual dysfunction [1,2]. An epidemiologic study revealed that hyperuricemia incidence showed an increasing and younger trend. Hyperuricemia pathogenesis includes excessive production and declined excretion. A background study showed that 90% of primary hyperuricemia cases resulted from declined excretion of urate from the kidneys [3]. 70% of serum uric acid is excreted from the kidneys [4], but 90–95% of uric acid can be reabsorbed into the blood [5]. Regulating the function of renal tubular urate transporters and inhibiting the reabsorption of urate is critical for hyperuricemia treatment

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