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Blanka Stiburkova, Dana Gabrikova, Pavel Čepek, Pavel Šimek, Pavol Kristian, Elizabeth Cordoba-Lanus, Felix Claverie-Martin
The Roma represents a transnational ethnic group, with a current European population of 8-10 million. The evolutionary process that had the greatest impact on the gene pool of the Roma population is called the founder effect. Renal hypouricemia (RHUC) is a rare heterogenous inherited disorder characterized by impaired renal urate reabsorption. The affected individuals are predisposed to recurrent episodes of exercise-induced nonmyoglobinuric acute kidney injury and nephrolithiasis. To date, more than 150 patients with a loss-of-function mutation for the SLC22A12 (URAT1) gene have been found, most of whom are Asians...
December 2016: Nucleosides, Nucleotides & Nucleic Acids
Makoto Hosoyamada, Yu Tsurumi, Hidenori Hirano, Naoko H Tomioka, Yuko Sekine, Takayuki Morisaki, Shunya Uchida
Renal hypouricemia (RHUC) is a hereditary disease characterized by a low level of plasma urate but with normal urinary urate excretion. RHUC type 1 is caused by mutations of the urate transporter URAT1 gene (SLC22A12). However, the plasma urate levels of URAT1 knockout mice are no different from those of wild-type mice. In the present study, a double knockout mouse, in which the URAT1 and uricase (Uox) genes were deleted (Urat1-Uox-DKO), were used as an experimental animal model of RHUC type 1 to investigate RHUC and excise-induced acute kidney injury (EIAKI)...
December 2016: Nucleosides, Nucleotides & Nucleic Acids
Michito Nagura, Yoshifuru Tamura, Takanori Kumagai, Makoto Hosoyamada, Shunya Uchida
Uric acid (UA) is a potential risk factor of the progression of chronic kidney disease (CKD). Recently, we reported that intestinal UA excretion might be enhanced via upregulation of the ATP-binding cassette transporter G2 (Abcg2) in a 5/6 nephrectomy (Nx) rat model. In the present study, we examined the mRNA and protein expressions of UA transporters, URAT1, GLUT9/URATv1, ABCG2 and NPT4 in the kidney and ileum in the same rat model. Additionally, we investigated the Abcg2 mRNA expression of ileum in hyperuricemic rat model by orally administering oxonic acid...
December 2016: Nucleosides, Nucleotides & Nucleic Acids
He Tian, Wei Liu, Zhixing Zhou, Qian Shang, Yuqiang Liu, Yafei Xie, Changying Liu, Weiren Xu, Lida Tang, Jianwu Wang, Guilong Zhao
In order to systematically explore and understand the structure-activity relationship (SAR) of a lesinurad-based hit (1c) derived from the replacement of the S atom in lesinurad with CH₂, 18 compounds (1a-1r) were designed, synthesized and subjected to in vitro URAT1 inhibitory assay. The SAR exploration led to the discovery of a highly potent flexible URAT1 inhibitor, 1q, which was 31-fold more potent than parent lesinurad (IC50 = 0.23 μM against human URAT1 for 1q vs 7.18 μM for lesinurad). The present study discovered a flexible molecular scaffold, as represented by 1q, which might serve as a promising prototype scaffold for further development of potent URAT1 inhibitors, and also demonstrated that the S atom in lesinurad was not indispensable for its URAT1 inhibitory activity...
November 16, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Kyoko Fujita, Kimiyoshi Ichida
A novel compound heterozygous mutation, including c.935_997delinsTGG, in exons 5/6 of SLC22A12 (URAT1) was identified in a patient with renal hypouricemia. This case expands the molecular mechanisms of renal hypouricemia, and suggests a potential relationship with exercise-induced renal failure.
December 1, 2016: Clinica Chimica Acta; International Journal of Clinical Chemistry
Tianqiao Yong, Minglong Zhang, Diling Chen, Ou Shuai, Shaodan Chen, Jiyan Su, Chunwei Jiao, Delong Feng, Yizhen Xie
ETHNOPHARMACOLOGICAL RELEVANCE: Cordyceps militaris was recorded in the classic traditional Chinese medicine book with the main functions of "protecting liver and enhancing kidney functions", influencing serum uric acid levels. AIM OF STUDY: The aim is to investigate the hypouricemic effects and possible mechanism of C. militaris in hyperuricemic mice. MATERIALS AND METHODS: A water extract (WECM) was prepared by decocting C. militaris directly at 80 (o)C in water bath, followed by lyophilization...
October 4, 2016: Journal of Ethnopharmacology
Jeffrey Miner, Philip K Tan, David Hyndman, Sha Liu, Cory Iverson, Payal Nanavati, David T Hagerty, Kimberly Manhard, Zancong Shen, Jean-Luc Girardet, Li-Tain Yeh, Robert Terkeltaub, Barry Quart
BACKGROUND: Excess body burden of uric acid promotes gout. Diminished renal clearance of uric acid causes hyperuricemia in most patients with gout, and the renal urate transporter (URAT)1 is important for regulation of serum uric acid (sUA) levels. The URAT1 inhibitors probenecid and benzbromarone are used as gout therapies; however, their use is limited by drug-drug interactions and off-target toxicity, respectively. Here, we define the mechanism of action of lesinurad (Zurampic®; RDEA594), a novel URAT1 inhibitor, recently approved in the USA and Europe for treatment of chronic gout...
October 3, 2016: Arthritis Research & Therapy
Philip K Tan, Traci M Ostertag, Jeffrey N Miner
Gout is caused by elevated serum urate levels, which can be treated using inhibitors of the uric acid transporter, URAT1. We exploited affinity differences between the human and rat transporters to map inhibitor binding sites in URAT1. Human-rat transporter chimeras revealed that human URAT1 serine-35, phenylalanine-365 and isoleucine-481 are necessary and sufficient to provide up to a 100-fold increase in affinity for inhibitors. Moreover, serine-35 and phenylalanine-365 are important for high-affinity interaction with the substrate urate...
October 7, 2016: Scientific Reports
Xiansheng Zhang, Jingwei Wu, Wei Liu, Yuqiang Liu, Yafei Xie, Qian Shang, Zhixing Zhou, Weiren Xu, Lida Tang, Jianwu Wang, Guilong Zhao
BACKGROUND: Gout is the most common inflammatory arthritis, which, if left untreated or inadequately treated, will lead to joint destruction, bone erosion and disability due to the crystal deposition. Uric acid transporter 1 (URAT1) was the promising therapeutic target for urate-lowering therapy. OBJECTIVE: The goal of this work is to understand the structure-activity relationship (SAR) of a potent lesinurad-based hit, sodium 2-((5-bromo-4-((4-cyclopropylnaphth-1-yl)methyl)-4H-1,2,4-triazol-3-yl)thio)acetate (1c), and based on that discover a more potent URAT1 inhibitor...
September 15, 2016: Medicinal Chemistry
Naoyuki Otani, Motoshi Ouchi, Keitaro Hayashi, Promsuk Jutabha, Naohiko Anzai
Organic anions (OAs) are secreted in renal proximal tubules in two steps. In the first step, OAs are transported from the blood through basolateral membranes into proximal tubular cells. The prototypical substrate for renal organic anion transport systems, para-aminohippurate (PAH), is transported across basolateral membranes of proximal tubular cells via OAT1 (SLC22A6) and OAT3 (SLC22A8) against an electrochemical gradient in exchange for intracellular dicarboxylates. In the second step, OAs exit into urine through apical membranes of proximal tubules...
September 10, 2016: Anatomical Science International
Ming Wang, Jing Zhao, Nan Zhang, Jianghua Chen
Astilbin is a flavonoid compound derived from the rhizome of Smilax china L. The effects and possible molecular mechanisms of astilbin on potassium oxonate-induced hyperuricemia mice were investigated in this study. Different dosages of astilbin (5, 10, and 20mg/kg) were administered to induce hyperuricemic mice. The results demonstrated that the serum uric acid (Sur) level was significantly decreased by increasing the urinary uric acid (Uur) level and fractional excretion of urate (FEUA) with astilbin, related with suppressing role in meditation of Glucose transporter 9 (GLUT9), Human urate transporter 1 (URAT1) expression and up-regulation of ABCG2, Organic anion transporter 1/3 (OAT1/3) and Organic cation transporter 1 (OCT1)...
August 11, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Rong Wang, Chun-Hua Ma, Fan Zhou, Ling-Dong Kong
The aim of the study was to investigate the effects of Siwu decoction on hyperuricemia, kidney inflammation, and dysfunction in hyperuricemic mice. Siwu decoction at 363.8, 727.5, and 1 455 mg·kg(-1) was orally administered to potassium oxonate-induced hyperuricemic mice for 7 days. Serum urate, creatinine, and blood urea nitrogen levels and hepatic xanthine oxidase (XOD) activity were measured. The protein levels of hepatic XOD and renal urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), organic anion transporters 1 (OAT1), ATP-binding cassette subfamily G member 2 (ABCG2), organic cation transporter 1 (OCT1), OCT2, organic cation/carnitine transporter 1 (OCTN1), OCNT2, Nod-like receptor family, pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), Caspase-1, and interleukin-1β (IL-1β) were determined by Western blotting...
July 2016: Chinese Journal of Natural Medicines
Ling-Dong Kong, Ying Pan
INTRODUCTION: Human urate transporter 1 (URAT1, encoded by SLC22A12) has been identified as a key urate transporter expressed at the apical membrane of renal proximal tubule cells for regulating urate homeostasis. Therefore, URAT1 is an attractive target for the development of new uricosurics against hyperuricemia. Discovery of novel inhibitors targeting URAT1 has become a research hotspot in recent years. AREAS COVERED: In this paper, we reviewed the patent applications and related research published during the years 2012-2015, covering the development of URAT1 inhibitors...
July 14, 2016: Expert Opinion on Therapeutic Patents
Philip K Tan, Jennifer E Farrar, Eric A Gaucher, Jeffrey N Miner
Uric acid is the highly insoluble end-product of purine metabolism in humans. Serum levels exceeding the solubility threshold can trigger formation of urate crystals resulting in gouty arthritis. Uric acid is primarily excreted through the kidneys with 90% reabsorbed back into the bloodstream through the uric acid transporter URAT1. This reabsorption process is essential for the high serum uric acid levels found in humans. We discovered that URAT1 proteins from humans and baboons have higher affinity for uric acid compared with transporters from rats and mice...
September 2016: Molecular Biology and Evolution
Vibha Bhatnagar, Erin L Richard, Wei Wu, Caroline M Nievergelt, Michael S Lipkowitz, Janina Jeff, Adam X Maihofer, Sanjay K Nigam
BACKGROUND: In the setting of chronic kidney disease (CKD), altered extra-renal urate handling may be necessary to regulate plasma uric acid. The Remote Sensing and Signaling Hypothesis (Nigam S. What do drug transporters really do? Nat Rev Drug Discov 2015; 14: 29-44) suggests that multispecific solute carrier (SLC) and ATP-binding cassette (ABC) drug transporters in different tissues are part of an inter-organ communication system that maintains levels of urate and other metabolites after organ injury...
June 2016: Clinical Kidney Journal
Pinky Dua, Rachel Gurrell, Simon Kirby, Maria Sudworth, Peter T Loudon
The objective of these clinical studies was to assess the safety and urate lowering activity of a novel urate transporter 1 (URAT1)/ xanthine oxidase (XO) inhibitor PF-06743649 in healthy subjects and gout patients. Escalating doses of PF-06743649 or placebo were given to healthy young subjects, healthy elderly subjects and gout patients. Serum uric acid (sUA) and urinary pharmacodynamic markers were assayed, and safety was assessed by collection of adverse events and assessment of safety labs, ECGs and vital signs...
August 2016: Clinical Rheumatology
Gleb Martovetsky, Kevin T Bush, Sanjay K Nigam
The hepatocyte nuclear factors, Hnf1a and Hnf4a, in addition to playing key roles in determining hepatocyte fate, have been implicated as candidate lineage-determining transcription factors in the kidney proximal tubule (PT) [Martovetsky et. al., (2012) Mol Pharmacol 84:808], implying an additional level of regulation that is potentially important in developmental and/or tissue-engineering contexts. Mouse embryonic fibroblasts (MEFs) transduced with Hnf1a and Hnf4a form tight junctions and express multiple PT drug transporters (e...
July 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Yusuke Okabayashi, Izumi Yamamoto, Yo Komatsuzaki, Takahito Niikura, Takafumi Yamakawa, Haruki Katsumata, Mayuko Kawabe, Ai Katsuma, Yasuyuki Nakada, Akimitsu Kobayashi, Yusuke Koike, Jun Miki, Hiroki Yamada, Yudo Tanno, Ichiro Ohkido, Nobuo Tsuboi, Kimiyoshi Ichida, Hiroyasu Yamamoto, Takashi Yokoo
We report a rare case of nephrocalcinosis caused by hereditary renal hypouricaemia 3 months after kidney transplantation. A 41-year-old man who underwent living-related kidney transplantation from his father was admitted to our hospital for a protocol biopsy; he had a serum creatinine (S-Cr) of 1.37 mg/dL and no proteinuria. Histologically, there was no evidence of rejection or calcineurin inhibitor toxicity, although scattered nephrocalcinosis was observed in the distal tubules. Perioperatively, the patient had a serum uric acid (S-UA) of 1...
July 2016: Nephrology
Kei Taniguchi, Yoshifuru Tamura, Takanori Kumagai, Shigeru Shibata, Shunya Uchida
BACKGROUND: Hypouricemia is pathognomonic in syndrome of inappropriate secretion of antidiuretic hormone (SIADH) but the underlying mechanism remains unclear. Based on the previous studies, we hypothesized that V1a receptor may play a principal role in inducing hypouricemia in SIADH and examined uric acid metabolism using a rat model. METHODS: Terlipressin (25 ng/h), a selective V1a agonist, was subcutaneously infused to 7-week-old male Wistar rats (n = 9). Control rats were infused with normal saline (n = 9)...
December 2016: Clinical and Experimental Nephrology
Sung Oh Ahn, Shuichi Ohtomo, Jumpei Kiyokawa, Toshito Nakagawa, Mizuki Yamane, Kyoung June Lee, Ki Hwan Kim, Byung Ho Kim, Jo Tanaka, Yoshiki Kawabe, Naoshi Horiba
Urate-lowering therapy is indispensable for the treatment of gout, but available drugs do not control serum urate levels tightly enough. Although the uricosurics benzbromarone and probenecid inhibit a urate reabsorption transporter known as renal urate transporter 1 (URAT1) and thus lower serum urate levels, they also inhibit other transporters responsible for secretion of urate into urine, which suggests that inhibiting URAT1 selectively would lower serum urate more effectively. We identified a novel potent and selective URAT1 inhibitor, UR-1102, and compared its efficacy with benzbromarone in vitro and in vivo...
April 2016: Journal of Pharmacology and Experimental Therapeutics
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