Pharmacological Basis for Use of a Novel Compound in Hyperuricemia: Anti-Hyperuricemic and Anti-Inflammatory Effects

Lei Zhao; Yihang Li; Dahong Yao; Ran Sun; Shifang Liu; Xi Chen; Congcong Lin; Jian Huang; Jinhui Wang; Guang Li

doi:10.3389/fphar.2021.772504

Pharmacological Basis for Use of a Novel Compound in Hyperuricemia: Anti-Hyperuricemic and Anti-Inflammatory Effects

Front Pharmacol. 2021 Nov 8:12:772504. doi: 10.3389/fphar.2021.772504. eCollection 2021.

Authors

Lei Zhao¹, Yihang Li^{2

3}, Dahong Yao^{1

4}, Ran Sun¹, Shifang Liu², Xi Chen^{2

3}, Congcong Lin¹, Jian Huang¹, Jinhui Wang¹, Guang Li^{2

3}

Affiliations

¹ Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, China.
² Yunnan Branch, Institute of Medicinal Plant, Chinese Academy of Medical Sciences, Peking Union Medical College, Jinghong, China.
³ Yunnan Key Laboratory of Southern Medicinal Utilization, Jinghong, China.
⁴ School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen, China.

Abstract

Background: The prevalence of hyperuricemia is considered high worldwide. Hyperuricemia occurs due to decreased excretion of uric acid, increased synthesis of uric acid, or a combination of both mechanisms. There is growing evidence that hyperuricemia is associated with a decline of renal function. Purpose: This study is aimed at investigating the effects of the novel compound on lowering the serum uric acid level and alleviating renal inflammation induced by high uric acid in hyperuricemic mice. Methods: Hyperuricemic mice model was induced by potassium oxonate and used to evaluate the effects of the novel compound named FxUD. Enzyme-linked immunosorbent assay was used to detect the related biochemical markers. Hematoxylin-eosin (HE) staining was applied to observe pathological changes. The mRNA expression levels were tested by qRT-PCR. The protein levels were determined by Western blot. In parallel, human proximal renal tubular epithelial cells (HK-2) derived from normal kidney was used to further validate the anti-inflammatory effects in vitro. Results: FxUD administration significantly decreased serum uric acid levels, restored the kidney function parameters, and improved the renal pathological injury. Meanwhile, treatment with FxUD effectively inhibited serum and liver xanthine oxidase (XOD) levels. Reversed expression alterations of renal inflammatory cytokines, urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) were observed in hyperuricemic mice. Western blot results illustrated FxUD down-regulated protein levels of inflammasome components. Further studies showed that FxUD inhibited the activation of NF-κB signaling pathway in the kidney of hyperuricemic mice. In parallel, the anti-inflammatory effect of FxUD was also confirmed in HK-2. Conclusion: Our study reveals that FxUD exhibits the anti-hyperuricemic and anti-inflammatory effects through regulating hepatic XOD and renal urate reabsorption transporters, and suppressing NF-κB/NLRP3 pathway in hyperuricemia. The results provide the evidence that FxUD may be potential for the treatment of hyperuricemia with kidney inflammation.

Keywords: NF-κB; NLRP3 inflammasome; hyperuricemia; urate reabsorption transporter; xanthine oxidase.