Betaine Reduces Serum Uric Acid Levels and Improves Kidney Function in Hyperuricemic Mice

Abstract

Betaine as a dietary alkaloid has attracted the attention of patients with kidney diseases. This study aimed to investigate the effects of betaine on serum uric acid levels and kidney function, and explore their underlying mechanisms in potassium oxonate-induced hyperuricemic mice. Betaine at 5, 10, 20, and 40 mg/kg was orally administered to hyperuricemic mice for 7 days and found to significantly reduce serum uric acid levels and increase fractional excretion of uric acid in hyperuricemic mice in a dose-dependent manner. It effectively restored renal protein level alterations of urate transport-related molecular proteins urate transporter 1, glucose transporter 9, organic anion transporter 1, and ATP-binding cassette subfamily G member 2 in this model, possibly resulting in the enhancement of kidney urate excretion. Moreover, betaine reduced serum creatinine and blood urea nitrogen levels and affected urinary levels of beta-2-microglobulin and N-acetyl-beta-D-glucosaminidase as well as upregulated renal protein levels of organic cation/carnitine transporters OCT1, OCTN1, and OCTN2, resulting in kidney function improvement in hyperuricemic mice. The findings from this study provide evidence that betaine has anti-hyperuricemic and nephroprotective actions by regulating protein levels of these renal organic ion transporters in hyperuricemic mice.

Key words

betaine - hyperuricemic mice - renal function - renal organic ion transporters

Publication History

Received: 28 May 2013

Accepted after revision: 08 November 2013

Article published online:
11 December 2013

• References

• 1 Becker MA, Jolly M. Hyperuricemia and associated diseases. Rheum Dis Clin North Am 2006; 32: 275-293
• 2 Anzai N, Miyazaki H, Noshiro R, Khamdang S, Chairoungdua A, Shin HJ, Enomoto A, Sakamoto S, Hirata T, Tomita K, Kanai Y, Endou H. The multivalent PDZ domain-containing protein PDZK1 regulates transport activity of renal urate-anion exchanger URAT1 via its C terminus. J Biol Chem 2004; 279: 45942-45950
• 3 Wakida N, Tuyen DG, Adachi M, Miyoshi T, Nonoguchi H, Oka T, Ueda O, Tazawa M, Kurihara S, Yoneta Y, Shimada H, Oda T, Kikuchi Y, Matsuo H, Hosoyamada M, Endou H, Otagiri M, Tomita K, Kitamura K. Mutations in human urate transporter 1 gene in presecretory reabsorption defect type of familial renal hypouricemia. J Clin Endocrinol Metab 2005; 90: 2169-2174
• 4 Preitner F, Bonny O, Laverrière A, Rotman S, Firsov D, Da Costa A, Metref S, Thorens B. Glut9 is a major regulator of urate homeostasis and its genetic inactivation induces hyperuricosuria and urate nephropathy. Proc Natl Acad Sci USA 2009; 106: 15501-15506
• 5 Vitart V, Rudan I, Hayward C, Gray NK, Floyd J, Palmer CNA, Knott SA, Kolcic I, Polasek O, Graessler J. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet 2008; 40: 437-442
• 6 Hediger MA, Johnson RJ, Miyazaki H, Endou H. Molecular physiology of urate transport. Physiology 2005; 20: 125-133
• 7 Eraly SA, Vallon V, Rieg T, Gangoiti JA, Wikoff WR, Siuzdak G, Barshop BA, Nigam SK. Multiple organic anion transporters contribute to net renal excretion of uric acid. Physiol Genom 2008; 33: 180-192
• 8 Woodward OM, Kottgen A, Coresh J, Boerwinkle E, Guggino WB, Kottgen M. Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proc Natl Acad Sci USA 2009; 106: 10338-10342
• 9 Iseki K, Oshiro S, Tozawa M, Iseki C, Ikemiya Y, Takishita S. Significance of hyperuricemia on the early detection of renal failure in a cohort of screened subjects. Hypertens Res 2001; 24: 691-697
• 10 Sun H, Frassetto L, Benet LZ. Effects of renal failure on drug transport and metabolism. Pharmacol Ther 2006; 109: 1-11
• 11 Deguchi T, Kusuhara H, Takadate A, Endou H, Otagiri M, Sugiyama Y. Characterization of uremic toxin transport by organic anion transporters in the kidney. Kidney Int 2004; 65: 162-174
• 12 Peltekova VD, Wintle RF, Rubin LA, Amos CI, Huang Q, Gu X, Newman B, Van Oene M, Cescon D, Greenberg G, Griffiths AM, St George-Hyslop PH, Siminovitch KA. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat Genet 2004; 36: 471-475
• 13 Huls M, van den Heuvel JJ, Dijkman HB, Russel FG, Masereeuw R. ABC transporter expression profiling after ischemic reperfusion injury in mouse kidney. Kidney Int 2006; 69: 2186-2193
• 14 Craig SA. Betaine in human nutrition. Am J Clin Nutr 2004; 80: 539-549
• 15 Olthof MR, Verhoef P. Effects of betaine intake on plasma homocysteine concentrations and consequences for health. Curr Drug Metab 2005; 6: 15-22
• 16 Abdelmalek MF, Sanderson SO, Angulo P, Soldevila-Pico C, Liu C, Peter J, Keach J, Cave M, Chen T, McClain CJ, Lindor KD. Betaine for nonalcoholic fatty liver disease: results of a randomized placebo-controlled trial. Hepatology 2009; 50: 1818-1826
• 17 Olthof MR, van Vliet T, Verhoef P, Zock PL, Katan MB. Effect of homocysteine-lowering nutrients on blood lipids: results from four randomised, placebo-controlled studies in healthy humans. Plos Med 2005; 2: e135
• 18 Zhan XA, Li JX, Xu ZR, Zhao RQ. Effects of methionine and betaine supplementation on growth performance, carcase composition and metabolism of lipids in male broilers. Br Poult Sci 2006; 47: 576-580
• 19 Ozturk F, Ucar M, Ozturk IC, Vardi N, Batcioglu K. Carbon tetrachloride-induced nephrotoxicity and protective effect of betaine in Sprague-Dawley rats. Urology 2003; 62: 353-356
• 20 Chen GL, Wei W, Xu SY. Effect and mechanism of total saponin of Dioscorea on animal experimental hyperuricemia. Am J Chin Med 2006; 34: 77-85
• 21 Wang CP, Wang Y, Wang X, Zhang X, Ye JF, Hu LS, Kong LD. Mulberroside a possesses potent uricosuric and nephroprotective effects in hyperuricemic mice. Planta Med 2011; 77: 786-794
• 22 Li JM, Zhang X, Wang X, Xie YC, Kong LD. Protective effects of cortex fraxini coumarines against oxonate-induced hyperuricemia and renal dysfunction in mice. Eur J Pharmacol 2011; 666: 196-204
• 23 Hu QH, Zhang X, Wang X, Jiao RQ, Kong LD. Quercetin regulates organic ion transporter and uromodulin expression and improves renal function in hyperuricemic mice. Eur J Nutr 2012; 51: 593-606
• 24 Jung YS, Kim SJ, Kwon DY, Ahn CW, Kim YS, Choi DW, Kim YC. Alleviation of alcoholic liver injury by betaine involves an enhancement of antioxidant defense via regulation of sulfur amino acid metabolism. Food Chem Toxicol 2013; 62?C: 292-298
• 25 Ozer JS, Dieterle F, Troth S, Perentes E, Cordier A, Verdes P, Staedtler F, Mahl A, Grenet O, Roth DR, Wahl D, Legay F, Holder D, Erdos Z, Vlasakova K, Jin H, Yu Y, Muniappa N, Forest T, Clouse HK, Reynolds S, Bailey WJ, Thudium DT, Topper MJ, Skopek TR, Sina JF, Glaab WE, Vonderscher J, Maurer G, Chibout SD, Sistare FD, Gerhold DL. A panel of urinary biomarkers to monitor reversibility of renal injury and a serum marker with improved potential to assess renal function. Nat Biotechnol 2010; 28: 486-494
• 26 Haring N, Mahr HS, Mundle M, Strohal R, Lhotta K. Early detection of renal damage caused by fumaric acid ester therapy by determination of urinary β2-microglobulin. Br J Dermatol 2011; 164: 648-651
• 27 Deuring JJ, de Haar C, Koelewijn CL, Kuipers EJ, Peppelenbosch MP, van der Woude CJ. Absence of ABCG2-mediated mucosal detoxification in patients with active inflammatory bowel disease is due to impeded protein folding. Biochem J 2012; 441: 87-93
• 28 Heemskerk S, Wouterse AC, Russel FG, Masereeuw R. Nitric oxide down-regulates the expression of organic cation transporters (OCT) 1 and 2 in rat kidney during endotoxemia. Eur J Pharmacol 2008; 584: 390-397
• 29 Mukherjee M, Latif ML, Pritchard DI, Bosquillon C. In-cell Western detection of organic cation transporters in bronchial epithelial cell layers cultured at an air-liquid interface on Transwell inserts. J Pharmacol Toxicol Methods 2013; 68: 184-189
• 30 Sjakste N, Baumane L, Boucher JL, Dzintare M, Meirena D, Sjakste J, Lauberte L, Kalvinsh I. Effects of gamma-butyrobetaine and mildronate on nitric oxide production in lipopolysaccharide-treated rats. Basic Clin Pharmacol Toxicol 2004; 94: 46-50
• 31 Nakanishi T, Burg MB. Osmoregulatory fluxes of myo-inositol and betaine in renal cells. Am J Physiol 1989; 257: C964-970
• 32 Moeckel GW, Lai LW, Guder WG, Kwon HM, Lien YH. Kinetics and osmoregulation of Na(+)-and Cl(−)-dependent betaine transporter in rat renal medulla. Am J Physiol 1997; 272: F100-F106
• 33 Iharada M, Miyaji T, Fujimoto T, Hiasa M, Anzai N, Omote H, Moriyama Y. Type 1 sodium-dependent phosphate transporter (SLC17A1 protein) is a Cl(−)-dependent urate exporter. J Biol Chem 2010; 285: 26107-26113
• 34 Wagner CA, Lukewille U, Kaltenbach S, Moschen I, Broer A, Risler T, Broer S, Lang F. Functional and pharmacological characterization of human Na(+)-carnitine cotransporter hOCTN2. Am J Physiol Renal Physiol 2000; 279: F584-F591
• 35 Nakanishi T, Hatanaka T, Huang W, Prasad PD, Leibach FH, Ganapathy ME, Ganapathy V. Na+-and Cl−-coupled active transport of carnitine by the amino acid transporter ATB (0,+) from mouse colon expressed in HRPE cells and Xenopus oocytes. J Physiol 2001; 532: 297-304
• 36 Choi HK, Liu S, Curhan G. Intake of purine-rich foods, protein, and dairy products and relationship to serum levels of uric acid: the third national health and nutrition examination survey. Arthritis Rheum 2005; 52: 283-289
• 37 Choi JW, Ford ES, Gao X, Choi HK. Sugar-sweetened soft drinks, diet soft drinks, and serum uric acid level: the Third National Health and Nutrition Examination Survey. Arthritis Rheum 2008; 59: 109-116
• 38 Lever M, George PM, Slow S, Elmslie JL, Scott RS, Richards AM, Fink JN, Chambers ST. Fibrates may cause an abnormal urinary betaine loss which is associated with elevations in plasma homocysteine. Cardiovasc Drugs Ther 2009; 23: 395-401
• 39 Storch KJ, Wagner DA, Young VR. Methionine kinetics in adult men: effects of dietary betaine on L-[2H3-methyl-1–13C] methionine. Am J Clin Nutr 1991; 54: 386-394
• 40 McGregor DO, Dellow WJ, Robson RA, Lever M, George PM, Chambers ST. Betaine supplementation decreases post-methionine hyperhomocysteinemia in chronic renal failure. Kidney Int 2002; 61: 1040-1046
• 41 Dellow WJ, Chambers ST, Lever M, Lunt H, Robson RA. Elevated glycine betaine excretion in diabetes mellitus patients is associated with proximal tubular dysfunction and hyperglycemia. Diabetes Res Clin Pract 1999; 43: 91-99
• 42 Schwab U, Alfthan G, Aro A, Uusitupa M. Long-term effect of betaine on risk factors associated with the metabolic syndrome in healthy subjects. Eur J Clin Nutr 2011; 65: 70-76
• 43 Abdelmalek MF, Angulo P, Jorgensen RA, Sylvestre PB, Lindor KD. Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. Am J Gastroenterol 2001; 96: 2711-2717
• 44 Slow S, Donaggio M, Cressey PJ, Lever M, George PM, Chambers ST. The betaine content of New Zealand foods and estimated intake in the New Zealand diet. J Food Compost Anal 2005; 18: 473-485
• 45 Perez-Ruiz F, Calabozo M, Erauskin GG, Ruibal A, Herrero-Beites AM. Renal underexcretion of uric acid is present in patients with apparent high urinary uric acid output. Arthritis Rheum 2002; 47: 610-613