New insight into the management of renal excretion and hyperuricemia: Potential therapeutic strategies with natural bioactive compounds

Bendong Yang, Meiling Xin, Shufei Liang, Xiaoxue Xu, Tianqi Cai, Ling Dong, Chao Wang, Meng Wang, Yuting Cui, Xinhua Song, Jinyue Sun, Wenlong Sun, Bendong Yang, Meiling Xin, Shufei Liang, Xiaoxue Xu, Tianqi Cai, Ling Dong, Chao Wang, Meng Wang, Yuting Cui, Xinhua Song, Jinyue Sun, Wenlong Sun

Abstract

Hyperuricemia is the result of increased production and/or underexcretion of uric acid. Hyperuricemia has been epidemiologically associated with multiple comorbidities, including metabolic syndrome, gout with long-term systemic inflammation, chronic kidney disease, urolithiasis, cardiovascular disease, hypertension, rheumatoid arthritis, dyslipidemia, diabetes/insulin resistance and increased oxidative stress. Dysregulation of xanthine oxidoreductase (XOD), the enzyme that catalyzes uric acid biosynthesis primarily in the liver, and urate transporters that reabsorb urate in the renal proximal tubules (URAT1, GLUT9, OAT4 and OAT10) and secrete urate (ABCG2, OAT1, OAT3, NPT1, and NPT4) in the renal tubules and intestine, is a major cause of hyperuricemia, along with variations in the genes encoding these proteins. The first-line therapeutic drugs used to lower serum uric acid levels include XOD inhibitors that limit uric acid biosynthesis and uricosurics that decrease urate reabsorption in the renal proximal tubules and increase urate excretion into the urine and intestine via urate transporters. However, long-term use of high doses of these drugs induces acute kidney disease, chronic kidney disease and liver toxicity. Therefore, there is an urgent need for new nephroprotective drugs with improved safety profiles and tolerance. The current systematic review summarizes the characteristics of major urate transporters, the mechanisms underlying the pathogenesis of hyperuricemia, and the regulation of uric acid biosynthesis and transport. Most importantly, this review highlights the potential mechanisms of action of some naturally occurring bioactive compounds with antihyperuricemic and nephroprotective potential isolated from various medicinal plants.

Keywords: chronic kidney disease; hyperuricemia; natural products; renal urate extraction; urate transporters.

Conflict of interest statement

SX and SW were employed by the Shandong Qingyujiangxing Biotechnology Co., Ltd. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Yang, Xin, Liang, Xu, Cai, Dong, Wang, Wang, Cui, Song, Sun and Sun.

Figures

FIGURE 1
FIGURE 1
Urate transporters and potential natural products for hyperuricemia treatment. URAT1, urate transporter 1; GLUT9, glucose transporter member 9; ABCG2, ATP-binding cassette transporter, subfamily G, member 2; OATs, organic anion transporters; NPTs, sodium-dependent phosphate cotransporter types. The activities of urate transporters were inhibited by benzbromarone (Mandal et al., 2017), probenecid (Mandal et al., 2017), tranilast (Mandal et al., 2017), losartan (Hamada et al., 2008; Miner et al., 2016b), lesinurad (Miner et al., 2016b), fenofibrate (Uetake et al., 2010), furosemide (Sato et al., 2010), respectively.

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