Abstract
BackgroundProlonged hyperuricemia is associated with kidney disease or gouty arthritis. Whether Yokuininto, a commercially available Kampo medicine that has been used for osteoarthritis or rheumatoid arthritis, can exhibit anti-hyperuricemic and inflammatory effects remains elusive. In the present study, Yokuininto exerts multiple homeostatic action on serum uric acid (sUA) levels by blocking pro-inflammatory cytokine activities and inducing uricosuric function with anti-renal injury functions.MethodsThe sUA was measured in potassium oxonate (PO)-administered mice. Renal transporter uptake assays were performed using HEK293 cells overexpressing OAT1, OCT2 or OAT3, MDCKII cells overexpressing BCRP, and Xenopus oocytes overexpressing OAT3 or URAT1. Immunoblot and ELISA assays were performed to detect the molecules (OAT3, GLUT9, XO, NGAL, KIM-1 and IL-1α) in various human kidney cell lines. Cell viability analysis was performed to evaluate the cytotoxicity of Yokuininto [Ephedrine + pseudoephedrine 21.94%; Paeoniflorin 35.40% and Liquiritin 16.21% relatively measured by the ratios (HR-MS2 intensity / HR-MS1 intensity)].ResultsYokuininto (300 mg/kg) significantly reduced sUA by approximately 44% compared to that of PO-induced mice. The OAT3 levels were decreased in PO-induced hyperuricemic condition, whereas the GLUT9 transporter levels were markedly increased. However, PO did not alter the levels of URAT1. Yokuininto significantly inhibited the lipopolysaccharide (LPS)-induced secretion of IL-1α by approximately 63.2% compared to the LPS-treated macrophages. In addition, Yokuininto inhibited nitric oxide synthesis by approximately 33.7 (500 µg/mL) and 64.6% (1000 µg/mL), compared to that of LPS-treated macrophages. Yokuininto markedly increased xanthine oxidase inhibition activity. Furthermore, interleukin-1α (IL-1α), a pro-inflammatory cytokine, elevated neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) activities in LLC-PK1 cells. Expression of renal inflammatory biomarkers, NGAL and KIM-1, was reduced under the Yokuininto treatment by 36.9 and 72.1%, respectively.ConclusionsThose results suggest that Yokuininto may suppress inflammation and protect against kidney dysfunction in hyperuricemia. The present findings demonstrated that Yokuininto lowered sUA through both increased uric acid excretion and decreased uric acid production. Our results may provide a basis for the protection of prolonged hyperuricemia-associated kidney injury with uric acid-lowering agents such as Yokuininto.
Highlights
Prolonged hyperuricemia is associated with kidney disease or gouty arthritis
To test the hypothesis that Yokuininto, a Kampo medicine that has been used for osteoarthritis [13] or rheumatoid arthritis [14], can be applied to treat hyperuricemia and gouty arthritis, we investigated the uric acid modulating effects of Yokuininto on serum level of uric acid, xanthine oxidase (XO) inhibiting activity, and organic anion transporter 3 (OAT3) and glucose transporter 9 (GLUT9) transporter activities
Compared to that of the untreated mice group, the serum level of uric acid in the potassium oxonate (PO)-induced mice was markedly increased by approximately 44.9% after PO administration
Summary
Prolonged hyperuricemia is associated with kidney disease or gouty arthritis. Yokuininto exerts multiple homeostatic action on serum uric acid (sUA) levels by blocking pro-inflammatory cytokine activities and inducing uricosuric function with anti-renal injury functions. Prolonged systemic hyperuricemia has been regarded as an etiology of gout and it causes inflammation and uric acid congestion in kidney cortex. Previous studies have reported that two basolateral membrane transporters, the organic anion transporter 3 (OAT3), which possesses secretory functions, and the glucose transporter 9 (GLUT9), which performs influx functions, are closely associated with the pathophysiology of hyperuricemia [4]. Interleukin-1 alpha (IL-1a) is a powerful inflammatory cytokine that regulates both adaptive and innate immunity. As such, it is implicated in the development of multiple autoimmune and inflammatory diseases such as arthritis. IL-1α can be found asa cell-bound molecule on the plasma membrane in epithelial cells and can be considered as tissue damage and begins triggering the early phases of gout flare with severe pains [7]
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