Inhibition Of Uric Acid-induced Expression Of URAT1 And GLUT9 By Fucoidan

Hyperuricemia is a syndrome characterized by purine metabolic disorder and high blood uric acid content in the body.Epidemiological investigation showed that hyperuricemia incidence has been observed an increasing and younger-age trend.The prevalence of hyperuricemia in China is distinguished by differences of gender,age and region.Male cases are more than females,the prevalence rate of male reaches the peak value in young adults,and female incidence before menopause is lower than male but almost equal to male after menopause.The prevalence rate in coastal cities is higher than that in inland cities,and that in urban region is higher than that in rural region.Hyperuricemia is a risk factor for many diseases,so prevention and treatment of hyperuricemia is urgent.At present,the drugs for the treatment of hyperuricemia are mostly synthetic drugs,which have toxicity and side effect,and other adverse reactions such as headache,nausea,vomiting,skin allergy,liver and kidney injury.Therefore,it is urgent to develop hypouricemic drugs with less side effects.Uric acid transporter 1(URAT1)and glucose transporter 9(GLUT9)are two important uric acid reabsorption proteins,which are important targets of drugs for hyperuricemia.Fucoidan sulfate(FPS)is a natural marine active substance with various biological activities.It has been used as a clinical drug for kidney disease for nearly 20 years.In recent years,studies have shown that FPS can reduce uric acid by inhibiting uric acid production and promoting renal excretion of uric acid,but its molecular mechanism is not clear.In this study,we investigated the mechanism of FPS inhibiting uric acid(UA)-mediated expression of URAT1 and GLUT9 in human renal tubular epithelial cells HK-2.In this study,we found that 200 μg/mL of UA promoted significantly expression of URAT1 and GLUT9 in HK-2 cells,but 25 μg/mL of FPS declined the expression level of URAT1 and GLUT9 in UA exposed cells to be normal content.The results showed that FPS should be beneficial for reducing UA reabsorption by inhibiting the expression of URAT1 and GLUT9 mediated by UA.Exposure of TLR4 inhibitor and NF-κB signaling pathway inhibitor resulted in expression reduction of URAT1 and GLUT9 in HK-2 cells,indicating that TLR4/NF-κB signaling pathway was involved in the regulation of UA mediated expression of URAT1 and GLUT9.FPS showed similar inhibitory effect,indicating that FPS could inhibit UA mediated URAT1 and GLUT9 gene expression by inhibiting TLR4/NF-κ B signaling pathway.Both PI3K/Akt signaling pathway inhibitor and JNK MAPK signaling pathway inhibitor downregulated the expression of URAT1 and GLUT9 in HK-2 cells exposed to UA,indicating that PI3K/Akt and JNK MAPK signaling pathways were involved in the regulation of UA mediated expression of URAT1 and GLUT9.FPS inhibited activation of Akt and JNK,and downregulated the expression levels of URAT1 and GLUT9 in UA exposed cells,indicating that FPS could inhibit UA mediated expression of URAT1 and GLUT9 by inhibiting PI3K/Akt and JNK MAPK signaling pathways.In conclusion,FPS can repress expression induction of URAT1 and GLUT9 in human renal tubular HK-2 cell by UA by inhibiting TLR4/NF-κB,PI3K/Akt and JNK MAPK signaling pathways.The results preliminarily explained the molecular mechanism of FPS promoting renal excretion of urate based on cellular and molecular level,and provided a theoretical basis for the research and development of FPS related anti-hyperuricemia drugs.