The kidney drug transporter OAT1 regulates gut microbiome–dependent host metabolism

Granados, Jeffry C.; Ermakov, V. N.; Maity, Koustav; Vera, David R.; Chang, Geoffrey; Nigám, Sanjay K.

doi:10.1172/jci.insight.160437

Cited by 5 publications

(15 citation statements)

References 79 publications

(129 reference statements)

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“…OAT1 is a drug transporter primarily present in the kidneys with a primary function of excreting uric acid [ 15 ]. HPRT1 is the most important enzyme in the purine remediation pathway.…”

Section: Resultsmentioning

confidence: 99%

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Analysis of Polyphenol Extract from Hazel Leaf and Ameliorative Efficacy and Mechanism against Hyperuricemia Zebrafish Model via Network Pharmacology and Molecular Docking

Wang,

Zhao,

Lin

et al. 2024

Molecules

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Hazel leaf, a by-product of hazelnuts, is commonly used in traditional folk medicine in Portugal, Sweden, Iran and other regions for properties such as vascular protection, anti-bleeding, anti-edema, anti-infection, and pain relief. Based on our previous studies, the polyphenol extract from hazel leaf was identified and quantified via HPLC fingerprint. The contents of nine compounds including kaempferol, chlorogenic acid, myricetin, caffeic acid, p-coumaric acid, resveratrol, luteolin, gallic acid and ellagic acid in hazel leaf polyphenol extract (ZP) were preliminary calculated, among which kaempferol was the highest with 221.99 mg/g, followed by chlorogenic acid with 8.23 mg/g. The inhibition of ZP on α-glucosidase and xanthine oxidase activities was determined via the chemical method, and the inhibition on xanthine oxidase was better. Then, the effect of ZP on hyperuricemia zebrafish was investigated. It was found that ZP obviously reduced the levels of uric acid, xanthine oxidase, urea nitrogen and creatinine, and up-regulated the expression ofOAT1 and HPRT genes in hyperuricemia zebrafish. Finally, the targeted network pharmacological analysis and molecular docking of nine polyphenol compounds were performed to search for relevant mechanisms for alleviating hyperuricemia. These results will provide a valuable basis for the development and application of hazel leaf polyphenols as functional ingredients.

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“…OAT1 is a drug transporter primarily present in the kidneys with a primary function of excreting uric acid [ 15 ]. HPRT1 is the most important enzyme in the purine remediation pathway.…”

Section: Resultsmentioning

confidence: 99%

“…Patients clinically lacking HPRT have varying degrees of gout and neurological disorders [ 26 ]. OAT1 (organic anion transporter 1) is a multispecific drug transporter in the kidneys involved in UA excretion [ 15 ]. In zebrafish, the similarities of HPRT and OAT1 genes with humans were 91% and 46%, respectively [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Analysis of Polyphenol Extract from Hazel Leaf and Ameliorative Efficacy and Mechanism against Hyperuricemia Zebrafish Model via Network Pharmacology and Molecular Docking

Wang,

Zhao,

Lin

et al. 2024

Molecules

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“…Many gut microbe–derived small molecules that appear to have properties of uremic toxins and signaling molecules (eg, pCS) are modified by liver enzymes and handled by OATs in the kidney. 70–73…”

Section: Gut-heart-kidney Cross Talk From the Viewpoint Of The Remote...mentioning

confidence: 99%

“…Many gut microbe-derived small molecules that appear to have properties of uremic toxins and signaling molecules (eg, pCS) are modified by liver enzymes and handled by OATs in the kidney. [70][71][72][73] Uric Acid, Hypertension, and CVD Uric acid has been associated with gout, kidney stones, metabolic syndrome, hypertension, and CVD. 64 Under normal conditions, about 70% of uric acid is handled by the kidneys with the rest managed mainly by the intestine.…”

Section: Indoxyl Sulfate and Cvdmentioning

confidence: 99%

“…70 The central role of these multispecific drug transporters in interfacing inter-organism communication between the kidney and gut bacteria has recently become clear. [71][72][73] Thus, remote sensing and signaling between the gut microbes, gut, liver (via phase I and phase II enzymes), and kidney (via OATs, AhRs or other mechanisms) regulates IxS, which is associated with heart disease. Many gut microbe-derived small molecules that appear to have properties of uremic toxins and signaling molecules (eg, pCS) are modified by liver enzymes and handled by OATs in the kidney.…”

Section: Indoxyl Sulfate and Cvdmentioning

confidence: 99%

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Role of the Microbiome in Gut-Heart-Kidney Cross Talk

Glorieux

Nigám

Vanholder

et al. 2023

Circulation Research

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Homeostasis is a prerequisite for health. When homeostasis becomes disrupted, dysfunction occurs. This is especially the case for the gut microbiota, which under normal conditions lives in symbiosis with the host. As there are as many microbial cells in and on our body as human cells, it is unlikely they would not contribute to health or disease. The gut bacterial metabolism generates numerous beneficial metabolites but also uremic toxins and their precursors, which are transported into the circulation. Barrier function in the intestine, the heart, and the kidneys regulates metabolite transport and concentration and plays a role in inter-organ and inter-organism communication via small molecules. This communication is analyzed from the perspective of the remote sensing and signaling theory, which emphasizes the role of a large network of multispecific, oligospecific, and monospecific transporters and enzymes in regulating small-molecule homeostasis. The theory provides a systems biology framework for understanding organ cross talk and microbe-host communication involving metabolites, signaling molecules, nutrients, antioxidants, and uremic toxins. This remote small-molecule communication is critical for maintenance of homeostasis along the gut-heart-kidney axis and for responding to homeostatic perturbations. Chronic kidney disease is characterized by gut dysbiosis and accumulation of toxic metabolites. This slowly impacts the body, affecting the cardiovascular system and contributing to the progression of kidney dysfunction, which in its turn influences the gut microbiota. Preserving gut homeostasis and barrier functions or restoring gut dysbiosis and dysfunction could be a minimally invasive way to improve patient outcomes and quality of life in many diseases, including cardiovascular and kidney disease.

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Effect of probenecid on blood levels and renal elimination of furosemide and endogenous compounds in rats: Discovery of putative organic anion transporter biomarkers

Thakur,

Saradhi Mettu,

Singh

et al. 2023

Biochemical Pharmacology

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The kidney drug transporter OAT1 regulates gut microbiome–dependent host metabolism

Cited by 5 publications

References 79 publications

Analysis of Polyphenol Extract from Hazel Leaf and Ameliorative Efficacy and Mechanism against Hyperuricemia Zebrafish Model via Network Pharmacology and Molecular Docking

Analysis of Polyphenol Extract from Hazel Leaf and Ameliorative Efficacy and Mechanism against Hyperuricemia Zebrafish Model via Network Pharmacology and Molecular Docking

Role of the Microbiome in Gut-Heart-Kidney Cross Talk

Effect of probenecid on blood levels and renal elimination of furosemide and endogenous compounds in rats: Discovery of putative organic anion transporter biomarkers

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