Impact of Lesinurad and Allopurinol on Experimental Hyperuricemia in Mice: Biochemical, Molecular and Immunohistochemical Study

Overview

Journal BMC Pharmacol Toxicol

Publisher Biomed Central

Specialty Pharmacology

Date 2020 Feb 12

PMID 32041665

Citations 8

Authors

Youssef Saeed Alghamdi

Mohamed Mohamed Soliman

Mohamed Abdo Nassan

Affiliations

Soon will be listed here.

Abstract

Background: Hyperuricemia is an abnormal increase in uric acid levels in the blood. It is the cause of gout that manifested by inflammatory arthritis and painful disable. Therefore, current study evaluated the potential ameliorative impact of Lesinurad and Allopurinol on the kidneys of hyperuricemic mice at the biochemical, molecular and cellular levels.

Methods: Lesinurad and allopurinol alone or in combination were orally administered to hyperuricemic and control mice for seven consecutive days. Levels of uric acid and blood urea nitrogen, along with antioxidants and inflammatory cytokines (IL-1β and TNF-α) were measured in the serum. The mRNA expression of mouse urate anion transporter-1, glucose transporter 9, organic anion transporters, in renal tissues were examined using quantitative real time PCR. Simultaneously, the immunoreactivity of transforming growth factor-beta 1 was examined immunohistochemically.

Results: Lesinurad and allopurinol administration resulted in significant decrease in serum levels of uric acid, blood urea nitrogen, xanthine oxidase activity, catalase, glutathione peroxidase and inflammatory cytokines (IL-1β and TNF-α) reported in hyperuricemic mice. Both partially reversed oxonate-induced alterations in renal mURAT-1, mGLUT-9, mOAT-1 and mOAT-3 expressions, as well as alterations in the immunoreactivity of TGF- β1, resulting in the increase of renal uric acid secretion and excretion. The combined administration of lesinurad and ALP restored all altered parameters in a synergistic manner, improving renal function in the hyperuricemic mouse model employed.

Conclusion: This study confirmed synergistic ameliorative hypouricemic impact of both lesinurad and allopurinol in the treatment of hyperuricemia in mice at the biochemical, molecular and cellular levels.

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References

Grayson P, Kim S, LaValley M, Choi H . Hyperuricemia and incident hypertension: a systematic review and meta-analysis. Arthritis Care Res (Hoboken). 2010; 63(1):102-10. PMC: 3016454. DOI: 10.1002/acr.20344. View

Saag K, Fitz-Patrick D, Kopicko J, Fung M, Bhakta N, Adler S . Lesinurad Combined With Allopurinol: A Randomized, Double-Blind, Placebo-Controlled Study in Gout Patients With an Inadequate Response to Standard-of-Care Allopurinol (a US-Based Study). Arthritis Rheumatol. 2016; 69(1):203-212. DOI: 10.1002/art.39840. View

Perez-Ruiz F, Jansen T, Tausche A, Juarez-Campo M, Karra Gurunath R, Richette P . Efficacy and safety of lesinurad for the treatment of hyperuricemia in gout. Drugs Context. 2019; 8:212581. PMC: 6544139. DOI: 10.7573/dic.212581. View

Vitart V, Rudan I, Hayward C, Gray N, Floyd J, Palmer C . SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet. 2008; 40(4):437-42. DOI: 10.1038/ng.106. View

Shen Z, Yeh L, Wallach K, Zhu N, Kerr B, Gillen M . In Vitro and In Vivo Interaction Studies Between Lesinurad, a Selective Urate Reabsorption Inhibitor, and Major Liver or Kidney Transporters. Clin Drug Investig. 2016; 36(6):443-52. PMC: 4891385. DOI: 10.1007/s40261-016-0386-y. View

Zamocky M, Regelsberger G, Jakopitsch C, Obinger C . The molecular peculiarities of catalase-peroxidases. FEBS Lett. 2001; 492(3):177-82. DOI: 10.1016/s0014-5793(01)02237-2. View

Smith E, Diaz-Torne C, Perez-Ruiz F, March L . Epidemiology of gout: an update. Best Pract Res Clin Rheumatol. 2011; 24(6):811-27. DOI: 10.1016/j.berh.2010.10.004. View

Romi M, Arfian N, Tranggono U, Setyaningsih W, Sari D . Uric acid causes kidney injury through inducing fibroblast expansion, Endothelin-1 expression, and inflammation. BMC Nephrol. 2017; 18(1):326. PMC: 5664905. DOI: 10.1186/s12882-017-0736-x. View

Lapi F, Azoulay L, Yin H, Nessim S, Suissa S . Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study. BMJ. 2013; 346:e8525. PMC: 3541472. DOI: 10.1136/bmj.e8525. View

10.

Terkeltaub R . Update on gout: new therapeutic strategies and options. Nat Rev Rheumatol. 2010; 6(1):30-8. DOI: 10.1038/nrrheum.2009.236. View

11.

Benn C, Dua P, Gurrell R, Loudon P, Pike A, Storer R . Physiology of Hyperuricemia and Urate-Lowering Treatments. Front Med (Lausanne). 2018; 5:160. PMC: 5990632. DOI: 10.3389/fmed.2018.00160. View

12.

Li L, Yang C, Zhao Y, Zeng X, Liu F, Fu P . Is hyperuricemia an independent risk factor for new-onset chronic kidney disease?: A systematic review and meta-analysis based on observational cohort studies. BMC Nephrol. 2014; 15:122. PMC: 4132278. DOI: 10.1186/1471-2369-15-122. View

13.

Zgaga L, Theodoratou E, Kyle J, Farrington S, Agakov F, Tenesa A . The association of dietary intake of purine-rich vegetables, sugar-sweetened beverages and dairy with plasma urate, in a cross-sectional study. PLoS One. 2012; 7(6):e38123. PMC: 3368949. DOI: 10.1371/journal.pone.0038123. View

14.

Zhu J, Qi X, Tan Y, Lyu X . [Dietary Factors Associated with Hyperuricemia and Glycolipid Metabolism Disorder in Middle-aged and Elderly People]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2016; 47(1):68-72. View

15.

Huneycutt E, Board C, Clements J . Lesinurad, a Selective URAT-1 Inhibitor With a Novel Mechanism in Combination With a Xanthine Oxidase Inhibitor, for Hyperuricemia Associated With Gout. J Pharm Pract. 2017; :897190017734427. DOI: 10.1177/0897190017734427. View

16.

Zamudio-Cuevas Y, Hernandez-Diaz C, Pineda C, Reginato A, Cerna-Cortes J, Ventura-Rios L . Molecular basis of oxidative stress in gouty arthropathy. Clin Rheumatol. 2015; 34(10):1667-72. DOI: 10.1007/s10067-015-2933-y. View

17.

Soliman M, Baiomy A, Yassin M . Molecular and Histopathological Study on the Ameliorative Effects of Curcumin Against Lead Acetate-Induced Hepatotoxicity and Nephrototoxicity in Wistar Rats. Biol Trace Elem Res. 2015; 167(1):91-102. DOI: 10.1007/s12011-015-0280-0. View

18.

Billiet L, Doaty S, Katz J, Velasquez M . Review of hyperuricemia as new marker for metabolic syndrome. ISRN Rheumatol. 2014; 2014:852954. PMC: 3945178. DOI: 10.1155/2014/852954. View

19.

Otani N, Ouchi M, Hayashi K, Jutabha P, Anzai N . Roles of organic anion transporters (OATs) in renal proximal tubules and their localization. Anat Sci Int. 2016; 92(2):200-206. DOI: 10.1007/s12565-016-0369-3. View

20.

Terkeltaub R . Gout in 2006: the perfect storm. Bull NYU Hosp Jt Dis. 2006; 64(1-2):82-6. View