Concentration-Dependent Inhibitory Effect of Irbesartan on Renal Uric Acid Transporters

AbstractElevated levels of uric acid, a metabolite of purine in humans, is related to various diseases, such as gout, atherosclerosis and renal dysfunction. The excretion and reabsorption of uric acid to/from urine is tightly regulated by uric acid transporters. The amino acid sequences of uric acid reabsorption transporters, URAT1/SLC22A12, OAT4/SLC22A11, and OAT10/SLC22A13, share closer phylogenic relationship, whereas the gene promoter sequences are distant phylogenic relationship. Through the single-cell RNA-sequencing analysis of an adult human kidney, we found that only a small number of cells express these transporters, despite their role in the regulation of serum uric acid levels. Transcriptional motif analysis on these transporter genes, revealed that the URAT1/SLC22A12 gene promoter displayed the most conserved estrogen response elements (EREs) among the three transporters. The endogenous selective estrogen receptor modulator (SERM) 27-hydroxycholesterol (27HC) had positive effects on the transcriptional activity of URAT1/SLC22A12. We also found that 27HC increased the protein and gene expression of URAT1/SLC22A12 in mouse kidneys and human kidney organoids, respectively. These results strongly suggest the role of 27HC for URAT1/SLC22A12 expression in renal proximal tubules and upregulation of serum uric acid levels and also show the relationship between cholesterol metabolism and serum uric acid regulation.Significance StatementThe elevated levels of serum uric acid cause various diseases, and the excretion/reabsorption of uric acid to/from urine is tightly regulated by the uric acid transporters. We found that despite the role in serum uric acid regulation, only a small number of cells express URAT1/SLC22A12. We also found that URAT1/SLC22A12 gene promoter region has effective estrogen response elements, and endogenous selective estrogen receptor (ER) modulator 27-hydroxycholesterol (27HC) increased URAT1/SLC22A12 expression in the mice kidneys and human kidney organoids. These suggest that 27HC increases URAT1/SLC22A12 expression and upregulate serum uric acid levels. Since 27HC connects cholesterol metabolism, our study indicates the important link between cholesterol metabolism and serum uric acid regulation, and also provides a novel therapeutic approach to hyperuricemia.

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A taxonomically-restricted Uric Acid transporter provides insight into antioxidant equilibrium

10.1101/287870 ◽

2018 ◽

Author(s):

Diogo Oliveira ◽

André Machado ◽

Tiago Cardoso ◽

Mónica Lopes-Marques ◽

L. Filipe C. Castro ◽

...

Keyword(s):

Ascorbic Acid ◽

Uric Acid ◽

Seminal Fluid ◽

Urogenital System ◽

The Novel ◽

Morphological Adaptations ◽

Gene Expression Quantification ◽

Uric Acid Transporters ◽

Clawed Frog

AbstractNucleobase-Ascorbate Transporter (NAT) family includes ascorbic acid, nucleobases and uric acid transporters, with a broad evolutionary distribution. In vertebrates, four members have been previously recognized, the ascorbate transporters Slc23a1 and Slc3a2, the nucleobase transporter Slc23a4 and an orphan transporter SLC23A3. Here we identify a fifth member of the vertebrateslc23complement (slc23a5), expressed in neopterygians (gars and teleosts) and amphibians, and clarify the evolutionary relationships between the novel gene and knownslc23genes. Further comparative analysis puts forward uric acid as the preferred substrate for Slc23a5. Gene expression quantification suggests kidney and testis as major expression sites inXenopus tropicalis(western clawed frog) andDanio rerio(zebrafish). Additional expression in brain was detected inD. rerio, while in the NeoteleosteiOryzias latipes(medaka)slc23a5expression is restricted to brain. The biological relevance of the retention of an extra transporter in fish and amphibians is examined: with respect to the (1) antioxidant role of uric and ascorbic acid in seminal fluid and brain, (2) the ability to endogenously synthesize ascorbic acid and (3) the morphological adaptations of the male urogenital system.

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Angiotensin II Receptor Blockers Induce Alteration of Serum Uric Acid Level via Renal Uric Acid Transporters. A Review of the Authors' Current Research

GOUT AND NUCLEIC ACID METABOLISM ◽

10.6032/gnam.33.149 ◽

2009 ◽

Vol 33 (2) ◽

pp. 149-162

Author(s):

Masanobu Sato ◽

Naohiko Anzai ◽

Ikumi Tamai

Keyword(s):

Uric Acid ◽

Angiotensin Ii ◽

Serum Uric Acid ◽

Uric Acid Level ◽

Acid Level ◽

Serum Uric Acid Level ◽

Angiotensin Ii Receptor Blockers ◽

Angiotensin Ii Receptor ◽

Receptor Blockers ◽

Uric Acid Transporters

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Function of Uric Acid Transporters and Their Inhibitors in Hyperuricaemia

Frontiers in Pharmacology ◽

10.3389/fphar.2021.667753 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hao-lu Sun ◽

Yi-wan Wu ◽

He-ge Bian ◽

Hui Yang ◽

Heng Wang ◽

...

Keyword(s):

Uric Acid ◽

Acid Level ◽

Acid Metabolism ◽

Serum Uric Acid Level ◽

The Body ◽

Vicious Cycle ◽

Theoretical Support ◽

Lipid Metabolism Disorders ◽

Acid Accumulation ◽

Uric Acid Transporters

Disorders of uric acid metabolism may be associated with pathological processes in many diseases, including diabetes mellitus, cardiovascular disease, and kidney disease. These diseases can further promote uric acid accumulation in the body, leading to a vicious cycle. Preliminary studies have proven many mechanisms such as oxidative stress, lipid metabolism disorders, and rennin angiotensin axis involving in the progression of hyperuricaemia-related diseases. However, there is still lack of effective clinical treatment for hyperuricaemia. According to previous research results, NPT1, NPT4, OAT1, OAT2, OAT3, OAT4, URAT1, GLUT9, ABCG2, PDZK1, these urate transports are closely related to serum uric acid level. Targeting at urate transporters and urate-lowering drugs can enhance our understanding of hyperuricaemia and hyperuricaemia-related diseases. This review may put forward essential references or cross references to be contributed to further elucidate traditional and novel urate-lowering drugs benefits as well as provides theoretical support for the scientific research on hyperuricemia and related diseases.

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Computational Analysis and Synthesis of Syringic Acid Derivatives as Xanthine Oxidase Inhibitors

Medicinal Chemistry ◽

10.2174/1573406415666191004134346 ◽

2020 ◽

Vol 16 (5) ◽

pp. 643-653 ◽

Cited By ~ 1

Author(s):

Neelam Malik ◽

Anurag Khatkar ◽

Priyanka Dhiman

Keyword(s):

Antioxidant Activity ◽

Uric Acid ◽

Molecular Docking ◽

Xanthine Oxidase ◽

Kinetic Studies ◽

Inhibitory Effect ◽

Syringic Acid ◽

Antioxidant Potential ◽

Xanthine Oxidase Inhibitors ◽

Analysis And Synthesis

Background: Xanthine oxidase (XO; EC 1.17.3.2) has been considered as a potent drug target for the cure and management of pathological conditions prevailing due to high levels of uric acid in the bloodstream. The role of xanthine oxidase has been well established in the generation of hyperuricemia and gout due to its important role in catalytic oxidative hydroxylation of hypoxanthine to xanthine and further catalyses of xanthine to generate uric acid. In this research, syringic acid, a bioactive phenolic acid was explored to determine the capability of itself and its derivatives to inhibit xanthine oxidase. Objective: The study aimed to develop new xanthine oxidase inhibitors from natural constituents along with the antioxidant potential. Methods: In this report, we designed and synthesized syringic acid derivatives hybridized with alcohol and amines to form ester and amide linkage with the help of molecular docking. The synthesized compounds were evaluated for their antioxidant and xanthine oxidase inhibitory potential. Results: Results of the study revealed that SY3 produces very good xanthine oxidase inhibitory activity. All the compounds showed very good antioxidant activity. The enzyme kinetic studies performed on syringic acid derivatives showed a potential inhibitory effect on XO ability in a competitive manner with IC50 value ranging from 07.18μM-15.60μM and SY3 was revealed as the most active derivative. Molecular simulation revealed that new syringic acid derivatives interacted with the amino acid residues SER1080, PHE798, GLN1194, ARG912, GLN 767, ALA1078 and MET1038 positioned inside the binding site of XO. Results of antioxidant activity revealed that all the derivatives showed very good antioxidant potential. Conclusion: Molecular docking proved to be an effective and selective tool in the design of new syringic acid derivatives .This hybridization of two natural constituents could lead to desirable xanthine oxidase inhibitors with improved activity.

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The anti-hyperuricemic effects of green alga Enteromorpha prolifera polysaccharide via regulation of the uric acid transporters in vivo

Food and Chemical Toxicology ◽

10.1016/j.fct.2021.112630 ◽

2021 ◽

pp. 112630

Author(s):

Xiaoqing Li ◽

Xiaoxiang Gao ◽

Hui Zhang ◽

Yuanyuan Liu ◽

Md Moklesur Rahman Sarker ◽

...

Keyword(s):

Uric Acid ◽

Green Alga ◽

Enteromorpha Prolifera ◽

Uric Acid Transporters

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The genetic basis of gout

10.1093/med/9780199668847.003.0040 ◽

2016 ◽

Author(s):

Tony R. Merriman

Keyword(s):

Uric Acid ◽

Genetic Variants ◽

Genetic Basis ◽

Histone Deacetylase Inhibitors ◽

Association Studies ◽

Genome Wide Association Studies ◽

Toll Like Receptor 4 ◽

Genome Wide ◽

Uric Acid Transporters ◽

Genetically Determined

An individual’s risk of gout is determined by a complex relationship between inherited genetic variants and environmental exposures. Genetic variants that control hyperuricaemia and subsequent progression to clinical gout specify pathogenic pathways that could be therapeutically targeted. Genome-wide association studies (GWAS) have provided novel insights into the pathways leading to hyperuricaemia. GWAS have identified the renal uric acid transporter SLC2A9/GLUT9 and the gut excretory molecule ABCG2, which each have very strong genetic effects in the control of urate levels and risk of gout. Histone deacetylase inhibitors are able to correct the genetically-determined ABCG2 dysfunction. Other renal uric acid transporters, such as SLC22A11/OAT4 and SLC22A12/URAT1 have been confirmed to be genetically associated with urate and the risk of gout. Genes that generate urate during glycolysis (e.g. GCKR) are also implicated. In contrast very little is known about genetic variants that control the progression from hyperuricaemia to gout with the toll-like receptor 4 gene being the only gene with replicated evidence of association.

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