The systems biology of uric acid transporters

Nigám, Sanjay K.; Bhatnagar, Vibha

doi:10.1097/mnh.0000000000000427

Cited by 76 publications

(42 citation statements)

References 66 publications

(114 reference statements)

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“…Excretion of UA is mainly determined by the balance between renal reabsorption and secretion, and the role of various urate transporters has been debated [8]. Usually, GLUT9, URAT1, OAT1, and OAT3 are the main transporters regulating renal urate handling, while ABCG2 appears to regulate intestinal transport [19]. For example, Vibha Bhatnagar et al pointed out that Chronic Renal Insufficiency Cohort data showed that GLUT9 played a much less significant role than ABCG2 in this subset of patients with CKD [20].…”

Section: Discussionmentioning

confidence: 99%

Effects of Chicory on Serum Uric Acid, Renal Function, and GLUT9 Expression in Hyperuricaemic Rats with Renal Injury and In Vitro Verification with Cells

Jin

Lin

Zhang

et al. 2018

Evidence-Based Complementary and Alternative Medicine

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Hyperuricaemia (HUA) is an independent risk factor for chronic kidney disease. Urate crystals are deposited in the kidney and can cause renal tubular interstitial fibrosis, leading to renal dysfunction. Chicory extract (hereafter referred to as chicory) clearly reduced serum uric acid levels in rats with HUA induced by 10% fructose. This is the first study to observe the effect of chicory on serum uric acid levels and renal function in rats with HUA and renal injury. In vivo studies using hyperuricaemic rats with renal injury induced by yeast and adenine demonstrated that chicory decreased serum uric acid level, and its effect of delaying the progression of kidney injury was better than that of benzbromarone. In vitro cell experiments showed that this effect is related to the inhibition of GLUT9 protein expression in renal tubules and that lowering blood uric acid concentrations is one of the factors that alleviates renal damage. The results of this study indicate that chicory can be used as an alternative for alleviating renal dysfunction in hyperuricaemia.

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Section: Discussionmentioning

confidence: 99%

Effects of Chicory on Serum Uric Acid, Renal Function, and GLUT9 Expression in Hyperuricaemic Rats with Renal Injury and In Vitro Verification with Cells

Jin

Lin

Zhang

et al. 2018

Evidence-Based Complementary and Alternative Medicine

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“…SLC22 transporters are among the best known drug transporters (OAT1, OAT3, OCT1, OCT2), but it is now clear from knockouts (including genome scale metabolic reconstructions of the knockouts) and human SNPs that their endogenous substrates include many metabolites, signaling molecules, gut microbiome products, antioxidants, vitamins and other physiologically important molecules 1,2,60–65 . Several metabolic diseases are associated with mutations or SNPs in SLC22 transporters 2,17,66 . There is a growing amount of evidence that SLC22 transporters such as OAT1 and OAT3 are important in the movement of metabolites through the gut-liver-kidney axis 10,12 .…”

Section: Resultsmentioning

confidence: 99%

A Network of SLC and ABC Transporter and DME Genes Involved in Remote Sensing and Signaling in the Gut-Liver-Kidney Axis

Rosenthal

Bush

Nigám

2019

Sci Rep

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Genes central to drug absorption, distribution, metabolism and elimination (ADME) also regulate numerous endogenous molecules. The Remote Sensing and Signaling Hypothesis argues that an ADME gene-centered network—including SLC and ABC “drug” transporters, “drug” metabolizing enzymes (DMEs), and regulatory genes—is essential for inter-organ communication via metabolites, signaling molecules, antioxidants, gut microbiome products, uremic solutes, and uremic toxins. By cross-tissue co-expression network analysis, the gut, liver, and kidney (GLK) formed highly connected tissue-specific clusters of SLC transporters, ABC transporters, and DMEs. SLC22, SLC25 and SLC35 families were network hubs, having more inter-organ and intra-organ connections than other families. Analysis of the GLK network revealed key physiological pathways (e.g., involving bile acids and uric acid). A search for additional genes interacting with the network identified HNF4α, HNF1α, and PXR. Knockout gene expression data confirmed ~60–70% of predictions of ADME gene regulation by these transcription factors. Using the GLK network and known ADME genes, we built a tentative gut-liver-kidney “remote sensing and signaling network” consisting of SLC and ABC transporters, as well as DMEs and regulatory proteins. Together with protein-protein interactions to prioritize likely functional connections, this network suggests how multi-specificity combines with oligo-specificity and mono-specificity to regulate homeostasis of numerous endogenous small molecules.

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“…These homeostatic networks can be sited within a single organ or involve several organs 20 . For example, three multi-specific transporters (OAT1, OAT3 and ABC subfamily G member 2 (ABCG2)) work closely with two limited-specificity transporters (URAT1 (also known as SLC22A12) and GLUT9 (also known as SLC2A9)) to control urate homeostasis 21 . In the absence of end-stage renal disease (ESRD), the bulk of urate handling in the kidney is carried out by these and several other transporters.…”

Section: Remote Sensing and Signalingmentioning

confidence: 99%

Uraemic syndrome of chronic kidney disease: altered remote sensing and signalling

2019

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Uremic syndrome (also known as uraemic syndrome) in patients with advanced chronic kidney disease involves the accumulation in plasma of small-molecule uremic solutes and uremic toxins (also known as uraemic toxins), dysfunction of multiple organs and dysbiosis of the gut microbiota. As such, uremic syndrome can be viewed as a disease of perturbed inter-organ and inter-organism (host–microbiota) communication. Multiple biological pathways are affected, including those controlled by solute carrier (SLC) and ATP-binding cassette (ABC) transporters and drug-metabolizing enzymes, many of which are also involved in drug absorption, distribution, metabolism and elimination (ADME). The remote sensing and signaling hypothesis identifies SLC and ABC transporter-mediated communication between organs and/or between the host and gut microbiota as key to the homeostasis of metabolites, antioxidants, signaling molecules, microbiota-derived products and dietary components in body tissues and fluid compartments. Thus, this hypothesis provides a useful perspective on the pathobiology of uremic syndrome. Pathways considered central to drug ADME might be particularly important for the body’s attempts to restore homeostasis, including the correction of disturbances due to kidney injury and the accumulation of uremic solutes and toxins. This Review discusses how the remote sensing and signaling hypothesis helps to provide a systems-level understanding of aspects of uremia that could lead to novel approaches to its treatment.

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The systems biology of uric acid transporters

Cited by 76 publications

References 66 publications

Effects of Chicory on Serum Uric Acid, Renal Function, and GLUT9 Expression in Hyperuricaemic Rats with Renal Injury and In Vitro Verification with Cells

Effects of Chicory on Serum Uric Acid, Renal Function, and GLUT9 Expression in Hyperuricaemic Rats with Renal Injury and In Vitro Verification with Cells

A Network of SLC and ABC Transporter and DME Genes Involved in Remote Sensing and Signaling in the Gut-Liver-Kidney Axis

Uraemic syndrome of chronic kidney disease: altered remote sensing and signalling

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