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Soluble Uric Acid Increases PDZK1 and ABCG2 Expression in Human

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Soluble Uric Acid Increases PDZK1 and ABCG2 Expression in Human Chen et al. Arthritis Research & Therapy (2018) 20:20 DOI 10.1186/s13075-018-1512-4 RESEARCHARTICLE Open Access Soluble uric acid increases PDZK1 and ABCG2 expression in human intestinal cell lines via the TLR4-NLRP3 inflammasome and PI3K/Akt signaling pathway Mo Chen1,2†, Xiaoyong Lu1†,CiLu1†, Ning Shen3, Yujie Jiang1, Menglu Chen1 and Huaxiang Wu1* Abstract Background: In addition to the kidney, the intestine is one of the most important organs involved in uric acid excretion. However, the mechanism of urate excretion in the intestine remains unclear. Therefore, the relationship between soluble uric acid and the gut excretion in human intestinal cells was explored. The relevant signaling molecules were then also examined. Methods: HT-29 and Caco-2 cell lines were stimulated with soluble uric acid. Western blotting and qRT-PCR were used to measure protein and mRNA levels. Subcellular fractionation methods and immunofluorescence were used to quantify the proteins in different subcellular compartments. Flow cytometry experiments examined the function of ATP-binding cassette transporter, subfamily G, member 2 (ABCG2). Small interfering RNA transfection was used to assess the interaction between ABCG2 and PDZ domain-containing 1 (PDZK1). Results: Soluble uric acid increased the expression of PDZK1 and ABCG2. The stimulation of soluble uric acid also facilitated the translocation of ABCG2 from the intracellular compartment to the plasma membrane and increased its transport activity. Moreover, the upregulation of PDZK1 and ABCG2 by soluble uric acid was partially decreased by either TLR4-NLRP3 inflammasome inhibitors or PI3K/Akt signaling inhibitors. Furthermore, PDZK1 knockdown significantly inhibited the expression and transport activity of ABCG2 regardless of the activation by soluble uric acid, demonstrating a pivotal role for PDZK1 in the regulation of ABCG2. Conclusions: These findings suggest that urate upregulates the expression of PDZK1 and ABCG2 for excretion in intestinal cells via activating the TLR4-NLRP3 inflammasome and PI3K/Akt signaling pathway. Keywords: Hyperuricemia, ABCG2, PDZK1, Intestine Background gout and hyperuricemia has been revealed by epidemio- Pathological hyperuricemia is defined as a serum urate logical investigations in several western countries [3, 4]. concentration (408 μmol/L) above which monosodium In Italy, the prevalence of hyperuricemia increased from urate (MSU) crystals form at physiological pH and 85.4 per 1000 inhabitants in 2005 to 119.3 per 1000 temperature [1]. Persistent hyperuricemia is widely con- inhabitants in 2009 [5]. Therefore, it is crucial to explore sidered the primary risk factor in several gout-associated the pathophysiological process of hyperuricemia and its diseases, such as gouty arthritis, gouty tophi, and renal effect on target organs. damage [2]. An increasing trend in the prevalence of Underexcretion is the main reason for hyperuricemia in patients with gout [6]. Renal excretion accounts for approximately two-thirds of urate excretion, whereas gut * Correspondence: [email protected]; [email protected] † excretion accounts for the rest [2, 7]. This process is Equal contributors 1Department of Rheumatology, Second Affiliated Hospital, School of regulated by a variety of apically and basolaterally Medicine, Zhejiang University, 310009 Hangzhou, China expressed reabsorptive and secretory transporters, some Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chen et al. Arthritis Research & Therapy (2018) 20:20 Page 2 of 12 of which could act as urate-lowering agents [7]. In the Methods gut, the secretory transporter ATP-binding cassette Reagents and antibodies transporter, subfamily G, member 2 (ABCG2) is crucial, Uric acid, lipopolysaccharide (LPS; from Escherichia coli and its reduced functioning leads to extra-renal 0111:B4), Brilliant Blue G, pyrrolidinedithiocarbamate underexcretion, resulting in a compensatory increase (PTDC), and HEPES were purchased from Sigma-Aldrich in renal urate output [8–11]. Therefore, it is essential (St. Louis, MO, USA). Wortmannin was purchased from to understand the functional and regulatory mechanisms MedChemExpress (Monmouth Junction, NJ, USA). of urate transport that could result in the development of Acetyl-YVAD-chloromethylketone and TAK242 were new medications to control urate levels, especially for purchased from Calbiochem (Rockland, MA, USA). patients with chronic renal failure. Pam3CSK4 was purchased from Tocris (Bristol, UK). PDZ domain-containing 1 (PDZK1) is a scaffold protein Antibodies against phosphorylated-Akt (p-Akt), Akt, that binds to several uric acid transporters and mediates caspase-1 P10, and caspase-1 P20 were obtained from Cell their subcellular localization [12–14]. A single-nucleotide Signaling Technology (Beverly, MA, USA). Antibodies polymorphism, rs12129861, in the PDZK1 gene is associ- against ABCG2, PDZK1, Na/K ATPase, Lamin A/C, ated with serum uric acid [15, 16]. Shimizu et al. [17] GAPDH, β-actin, TLR2, TLR4, MYD88, P2X7, ASC, and reported that the expression of ABCG2 in the intestinal nuclear factor-κB(NF-κB) were obtained from Santa Cruz brush-border membranes was reduced in Pdzk1-knockout Biotechnology (Santa Cruz, CA, USA). Penicillin/strepto- mice, suggesting that PDZK1 is significantly associated mycin and TRIzol reagent were purchased from Invitro- with the apical localization of ABCG2. gen Life Technologies (Carlsbad, CA, USA). The clinical features of gout occur as a result of the inflammatory response to MSU crystals [2]. Accumulat- Cell culture ing evidence has demonstrated that MSU crystal- HT-29 and Caco-2 human intestinal cell lines were induced inflammation is a paradigm of innate immunity purchased from the Cell Bank of the Chinese Academy in gout [18]. Moreover, this inflammatory response is of Sciences (Shanghai, China) and cultured in RPMI initiated when MSU crystals engaged the caspase-1-ac- 1640 and high-glucose Dulbecco’s modified Eagle’s tivating NOD-like receptor superfamily pyrin domain- medium (DMEM) (Invitrogen) containing 10% fetal containing 3 (NLRP3) inflammasome, resulting in the bovine serum (FBS; Gibco, Adelaide, Australia). Cells β production of active interleukin-1 and interleukin-18. were grown in a humidified incubator containing 5% [19]. However, hyperuricemia is necessary but not CO2 at 37 °C. sufficient for gout. Recent findings suggest that the During the experiments, a growth arrest period in presence of elevated soluble serum uric acid may also serum-free medium was observed overnight prior to exert proinflammatory effects, even in the absence of gout stimulation. Cells were then treated with uric acid or the – [20 23]. Soluble uric acid increases NLRP3 inflamma- solvent (10 mM NaOH) after the addition of HEPES at a some activation in human primary renal proximal tubule final concentration of 25 mM. The solution was filtered – epithelial cells [24 26]. However, little is known concern- through a 0.22-μm pore size filter (Millipore, Shanghai, ing the effects and molecular mechanisms of uric acid in China) before use. the intestines. The aim of this article is to explore the relationship between soluble uric acid and gut excretion as well as Cellular stimulation conditions the relevant mechanisms. In this study, HT-29 and The inhibitors were dissolved in DMSO or dd H2O. Cells Caco-2 cells were used as well-established models of were pretreated with the corresponding inhibitors in a human intestinal epithelial cells to examine the human humidified incubator containing 5% CO2 at 37 °C before intestinal transport mechanism. The results indicate that stimulation with soluble uric acid. The final concentrations soluble uric acid increased the expression of PDZK1 and and incubation times were as follows: Brilliant Blue G (50 μ μ ABCG2 via the TLR4-NLRP3 inflammasome and nM,6h),PTDC(100 M, 2 h), Wortmanning (3 g/ml, 2 μ phosphatidylinositol-4, 5-bisphosphate 3/kinase (PI3K)/ h), acetyl-YVAD-chloromethylketone (20 M, 2 h), μ μ protein kinase B (Akt) signaling pathway in HT-29 and TAK242 (2 M, 2 h), Pam3CSK4 (5 g/ml,2h),and μ Caco-2 cells. Stimulation of soluble uric acid also LPS (1 g/ml, 6 h). facilitated the translocation of ABCG2 from the intracel- lular compartment to the plasma membrane and Extraction of subcellular fractions increased its transport activity. An additional study, For total protein extraction, cells were washed with ice- which was carried out to examine the possible inter- cold phosphate-buffered saline (PBS) and lysed in radio- action between PDZK1 and ABCG2, indicated that immunoprecipitation assay lysis buffer supplemented with PDZK1 plays a pivotal role in the regulation of ABCG2. a proteasome inhibitor (Beyotime, Shanghai, China). Chen et al. Arthritis Research & Therapy (2018) 20:20 Page 3 of 12 Nuclear and cytoplasmic extractions were prepared incubated with a rabbit ABCG2 antibody (1:40) or a using an NE-PER Nuclear
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