Hypouricemic and Nephroprotective Effects of Emodinol in Oxonate-Induced Hyperuricemic Mice are Mediated by Organic Ion Transporters and OIT3

Abstract

Emodinol, 1β,3β,23-trihydroxyolean-12-en-28-acid, as the main active ingredient firstly extracted from the rhizomes of Elaeagus pungens by our research group, has been demonstrated to exhibit uricosuric activity by our previous study. The aim of this study was to evaluate the uricosuric and nephroprotective effects of emodinol and explore its possible mechanisms in potassium oxonate-induced hyperuricemic mice with renal dysfunction. Mice were orally administrated 250 mg/kg of potassium oxonate once daily for 7 consecutive days to induce hyperuricemia with renal dysfunction. Emodinol was given at doses of 25, 50, and 100 mg/kg on the same day 1 h after oxonate treatment, and allopurinol (10 mg/kg) was given as a positive control. After 1 week, serum uric acid, serum creatinine, urine uric acid, urine creatinine, blood urea nitrogen, and hepatic xanthine oxidase activity were determined. The mRNA and protein levels of urate transporter 1, glucose transporter 9, ATP-binding cassette subfamily G member 2, organic anion transporter 1, oncoprotein-induced transcript 3, and organic cation/carnitine transporters in the kidney were detected by real-time polymerase chain reaction and Western blot analysis. In addition, urinary and renal Tamm-Horsfall glycoprotein concentrations were examined by ELISA assays. Emodinol significantly reduced serum urate levels, increased urinary urate levels and fractional excretion of uric acid, and inhibited hepatic xanthine oxidase activity in hyperuricemic mice. Moreover, potassium oxonate administration led to dys expressions of renal urate transporter 1, glucose transporter 9, ATP-binding cassette subfamily G member 2, organic anion transporter 1, and oncoprotein-induced transcript 3 as well as alternations of uromodulin concentrations, which could be reversed by emodinol. On the other hand, treatment of emodinol caused upregulated expressions of organic cation/carnitine transporters, resulting in an improvement of renal function characterized by decreased serum creatinine and blood urea nitrogen levels. Emodinol exhibited hypouricemic and nephroprotective actions by inhibiting xanthine oxidase activity and regulating renal ion transporters and oncoprotein-induced transcript 3, which may be a potential therapeutic agent in hyperuricemia and renal dysfunction.

Key words

Elaeagnus pungens - Elegeanaceae - emodinol - hyperuricemia - renal dysfunction - renal organic ion transporters - OIT3

• References

• 1 Karis E, Crittenden DB, Pillinger MH. Hyperuricemia, gout, and related comorbidities: cause and effect on a two-way street. South Med J 2014; 107: 235-241
• 2 Toda A, Ishizaka Y, Tani M, Yamakado M. Hyperuricemia is a significant risk factor for the onset of chronic kidney disease. Nephron Clin Pract 2014; 126: 33-38
• 3 Micaela G, Natalia M, Saverio M, Vincenzo M. The treatment of hyperuricemia. Int J Cardiol DOI: 10.1016/j.ijcard.2015.08.087. advance online publication 8 August 2015
• 4 Ichida K, Matsuo H, Takada T, Nakayama A, Murakami K, Shimizu T, Yamanashi Y, Kasuga H, Nakashima H, Nakamura T, Takada Y, Kawamura Y, Inoue H, Okada C, Utsumi Y, Ikebuchi Y, Ito K, Nakamura M, Shinohara Y, Hosoyamada M, Sakurai Y, Shinomiya N, Hosoya T, Suzuki H. Decreased extra-renal urate excretion is a common cause of hyperuricemia. Nat Commun 2012; 3: 764
• 5 Anzai N, Jutabha P, Amonpatumrat-Takahashi S, Sakurai H. Recent advances in renal urate transport: characterization of candidate transporters indicated by genome-wide association studies. Clin Exp Nephrol 2012; 16: 89-95
• 6 Masereeuw R, Russel FG. Therapeutic implications of renal anionic drug transporters. Pharmacol Ther 2010; 126: 200-216
• 7 Sato M, Wakayama T, Mamada H, Shirasaka Y, Nakanishi T, Tamai I. Identification and functional characterization of uric acid transporter Urat1 (Slc22a12) in rats. Biochim Biophys Acta 2011; 1808: 1441-1447
• 8 Mueckler M, Thorens B. The SLC2 (GLUT) family of membrane transporters. Mol Aspects Med 2013; 34: 121-138
• 9 Nakanishi T, Ohya K, Shimada S, Anzai N, Tamai I. Functional cooperation of URAT1 (SLC22A12) and URATv1 (SLC2A9) in renal reabsorption of urate. Nephrol Dial Transplant 2013; 28: 603-611
• 10 Stiburkova B, Sebesta I, Ichida K, Nakamura M, Hulkova H, Krylov V, Kryspinova L, Jahnova H. Novel allelic variants and evidence for a prevalent mutation in URAT1 causing renal hypouricemia: biochemical, genetics and functional analysis. Eur J Hum Genet 2013; 21: 1067-1073
• 11 Mou LJ, Jiang LP, Hu Y. A novel homozygous GLUT9 mutation cause recurrent exercise-induced acute renal failure and posterior reversible encephalopathy syndrome. J Nephrol 2015; 28: 387-392
• 12 Nakayama A, Matsuo H, Takada T, Ichida K, Nakamura T, Ikebuchi Y, Ito K, Hosoya T, Kanai Y, Suzuki H, Shinomiya N. ABCG2 is a high-capacity urate transporter and its genetic impairment increases serum uric acid levels in humans. Nucleosides Nucleotides Nucleic Acids 2011; 30: 1091-1097
• 13 Hu QH, Zhu JX, Ji J, Wei LL, Miao MX, Ji H. Fructus gardenia extract ameliorates oxonate-induced hyperuricemia with renal dysfunction in mice by regulating organic ion transporters and mOIT3. Molecules 2013; 18: 8976-8993
• 14 Mao S, Zhang A, Huang S. The signaling pathway of uromodulin and its role in kidney diseases. J Recept Signal Transduct Res 2014; 34: 440-444
• 15 Wei X, Xu R, Yang Z, Li Z, Liao Y, Johnson RJ, Yu X, Chen W. Novel uromodulin mutation in familial juvenile hyperuricemic nephropathy. Am J Nephrol 2012; 36: 114-120
• 16 Lipkowitz MS. Regulation of uric acid excretion by the kidney. Curr Rheumatol Rep 2012; 14: 179-188
• 17 Yan B, Zhang ZZ, Huang LY, Shen HL, Han ZG. OIT3 deficiency impairs uric acid reabsorption in renal tubule. FEBS Lett 2012; 586: 760-765
• 18 Koepsell H. The SLC22 family with transporters of organic cations, anions and zwitterions. Mol Aspects Med 2013; 34: 413-435
• 19 Jalal DI, Chonchol M, Chen W, Targher G. Uric acid as a target of therapy in CKD. Am J Kidney Dis 2013; 61: 134-146
• 20 Ciarimboli G. Membrane transporters as mediators of cisplatinside side-effects. Anticancer Res 2014; 34: 547-550
• 21 Tamai I. Pharmacological and pathophysiological roles of carnitine/organic cation transporters (OCTNs: SLC22A4, SLC22A5 and Slc22a21). Biopharm Drug Dispos 2013; 34: 29-44
• 22 Lou Y, Li J, Lu Y, Wang X, Jiao R, Wang S, Kong L. Aristolochic acid-induced destruction of organic ion transporters and fatty acid metabolic disorder in the kidney of rats. Toxicol Lett 2011; 201: 72-79
• 23 Pelis RM, Wright SH. SLC22, SLC44, and SLC47 transporters–organic anion and cation transporters: molecular and cellular properties. Curr Top Membr 2014; 73: 233-261
• 24 Stamp LK, Taylor WJ, Jones PB, Dockerty JL, Drake J, Frampton C, Dalbeth N. Starting dose is a risk factor for allopurinol hypersensitivity syndrome: a proposed safe starting dose of allopurinol. Arthritis Rheum 2012; 64: 2529-2536
• 25 van EchteldI A, van Durme C, Falzon L, Landewé RB, van der Heijde DM, Aletaha D. Treatment of gout patients with impairment of renal function: a systematic literature review. J Rheumatol Suppl 2014; 92: 48-54
• 26 Cheng CL, Chao PH, Hsu JC, Weng MM, On AW, Yang YH. Utilization patterns of antihyperuricemic agents following safety announcement on allopurinol and benzbromarone by Taiwan Food and Drug Administration. Pharmacoepidemiol Drug Saf 2014; 23: 309-313
• 27 Yang ZL. The preparation and application of Elaeagnus pungens extracts. CN Patent 201110166570.4, 2011
• 28 Bobulescu IA, Moe OW. Renal transport of uric acid: evolving concepts and uncertainties. Adv Chronic Kidney Dis 2012; 19: 358-371
• 29 Wang CP, Wang Y, Wang X, Zhang X, Ye JF, Hu LS, Kong LD. Mulberroside possesses potent uricosuric and nephroprotective effects in hyperuricemic mice. Planta Med 2011; 77: 786-794
• 30 Fu W, Li Q, Yao J, Zheng J, Lang L, Li W, Yan J. Protein expression of urate transporters in renal tissue of patients with uric acid nephrolithiasis. Cell Biochem Biophys 2014; 70: 449-454
• 31 Chiba T, Matsuo H, Nagamori S, Nakayama A, Kawamura Y, Shimizu S, Sakiyama M, Hosoyamada M, Kawai S, Okada R, Hamajima N, Kanai Y, Shinomiya N. Identification of a hypouricemia patient with SLC2A9 R380 W, a pathogenic mutation for renal hypouricemia type 2. Nucleosides Nucleotides Nucleic Acids 2014; 33: 261-265
• 32 Yano H, Tamura Y, Kobayashi K, Tanemoto M, Uchida S. Uric acid transporter ABCG2 is increased in the intestine of the 5/6 nephrectomy rat model of chronic kidney disease. Clin Exp Nephrol 2014; 18: 50-55
• 33 Komazawa H, Yamaguchi H, Hidaka K, Ogura J, Kobayashi M, Iseki K. Renal uptake of substrates for organic anion transporters Oat1 and Oat3 and organic cation transporters Oct1 and Oct2 is altered in rats with adenine-induced chronic renal failure. J Pharm Sci 2013; 102: 1086-1094
• 34 Chen L, Lan Z, Ma S, Zhao L, Yang X. Attenuation of gouty arthritis by emodinol in monosodium urate crystal-treated mice. Planta Med 2013; 79: 634-638
• 35 George RL, Keenan RT. Genetics of hyperuricemia and gout: implications for the present and future. Curr Rheumatol Rep 2013; 15: 309
• 36 Reginato AM, Mount DB, Yang I, Choi HK. The genetics of hyperuricaemia and gout. Nat Rev Rheumatol 2012; 8: 610-621
• 37 Al-Shibli A, Al Tatari H, Al Ameri A, Ghatasheh G, Issah M, Al Attrach I, Narchi H. Uric acid excretion in rotavirus gastro-enteritis. Paediatr Int Child Health 2014; 34: 19-23
• 38 Meng Z, Yan Y, Tang Z, Guo C, Li N, Huang W, Ding G, Wang Z, Xiao W, Yang Z. Anti-hyperuricemic and nephroprotective effects of rhein in hyperuricemic mice. Planta Med 2015; 81: 279-285
• 39 Chen L, Lan Z, Zhou Y, Li F, Zhang X, Zhang C, Yang Z, Li P. Astilbin attenuates hyperuricemia and ameliorates nephropathy in fructose-induced hyperuricemic rats. Planta Med 2011; 77: 1769-1773
• 40 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