Glucose Transporter 9 (GLUT9) Plays an Important Role in the Placental Uric Acid Transport System

Lüscher, Benjamin P.; Albrecht, Christiane; Stieger, Bruno; Surbek, Daniel; Baumann, Marc

doi:10.3390/cells11040633

Cited by 8 publications

(6 citation statements)

References 24 publications

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“…In the first gestational week, corresponding to the first trimester of human pregnancy, wild-type (WT) mice and LG9KO mice showed similar mean arterial pressure (MAP) values ( Figure 1 A). During the second gestational week, blood pressure dropped in both groups, which occurs commonly during the second trimester in humans as well as in mice [ 28 ]. This drop, however, was smaller in the LG9KO mice than in WT mice, leading to significantly higher blood pressure values in the LG9KO mice compared with WT mice.…”

Section: Resultsmentioning

confidence: 99%

“…Since uric acid has no access to the liver enzyme uricase and, in turn, cannot be metabolized in G9KO fetuses, the only way to eliminate uric acid from fetal circulation is via transplacental transport. We have previously shown that the placenta efficiently maintains uric acid equilibrium between maternal and fetal circulation [ 28 ]. Placental GLUT9 plays a major role in fetal uric acid homeostasis since G9KO fetuses (lacking hepatic and placental GLUT9) show substantially higher uric acid serum levels than their mothers.…”

Section: Discussionmentioning

confidence: 99%

“…In the kidney, GLUT 9a is expressed on the basolateral side of the proximal tubule, while GLUT9b is expressed on the apical side of the collecting duct [ 27 ]. Placental GLUT9a and GLUT9b however co-localize with the villous (apical) membrane but not with the basal membrane of the syncytiotrophoblast [ 28 ]. The simultaneous presence of GLUT9a and GLUT9b in the microvillus membrane of syncytiotrophoblasts may enhance clearing the syncytial epithelium and, in turn, facilitate the uric acid transport from the fetoplacental unit into the maternal circulation.…”

Section: Introductionmentioning

confidence: 99%

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Hyperuricemia during Pregnancy Leads to a Preeclampsia-Like Phenotype in Mice

Lüscher

Schoeberlein

Surbek

et al. 2022

Cells

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Hyperuricemia is a common feature in pregnancies compromised by pre-eclampsia, a pregnancy disease characterized by hypertension and proteinuria. The role of uric acid in the pathogenesis of pre-eclampsia remains largely unclear. The aim of this study was to investigate the effect of elevated uric acid serum levels during pregnancy on maternal blood pressure and neonatal outcome using two different murine knockout models. Non-pregnant liver-specific GLUT9 knockout (LG9KO) mice showed elevated uric acid serum concentrations but no hypertensive blood pressure levels. During pregnancy, however, blood pressure levels of these animals increased in the second and third trimester, and circadian blood pressure dipping was severely altered when compared to non-pregnant LG9KO mice. The impact of hyperuricemia on fetal development was investigated using a systemic GLUT9 knockout (G9KO) mouse model. Fetal hyperuricemia caused distinctive renal tissue injuries and, subsequently an impaired neonatal growth pattern. These findings provide strong evidence that hyperuricemia plays a major role in the pathogenesis of hypertensive pregnancy disorders such as pre-eclampsia. These novel insights may enable the development of preventive and therapeutic strategies for hyperuricemia-related diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hyperuricemia during Pregnancy Leads to a Preeclampsia-Like Phenotype in Mice

Lüscher

Schoeberlein

Surbek

et al. 2022

Cells

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“…The deletion of the URAT1 gene results in a notable decrease in the reabsorption and excretion of UA, consequently precipitating renal hyperuricemia and the onset of gout ( Kuo et al, 2017 ). GLUT9, found in both the basal and apical membranes of the renal proximal tubule, also accounts for the reabsorption of UA ( Auberson et al, 2018 ), playing a crucial role in the renal process of UA excretion ( Lüscher et al, 2022 ). Moreover, knockout mice of SLC2A9 demonstrate impaired enterocyte urate transport kinetics coupled with elevated serum urate concentration ( Novikov et al, 2019 ).…”

Section: The Uric Acid Transporter Of Tcm In the Treatment Of Goutmentioning

confidence: 99%

TCM and related active compounds in the treatment of gout: the regulation of signaling pathway and urate transporter

Sun,

Yang,

Sun

et al. 2023

Front. Pharmacol.

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Gout represents a metabolic ailment resulting from the accumulation of monosodium urate crystals within joints, causing both inflammation and, harm to tissues. The primary contributor to gout’s emergence is an elevated presence of serum urate, which is under the regulation of kidney and, gut urate transporters. Mitigating this risk factor is crucial for averting gout’s onset. Several treatments rooted in TCM and related active compounds have demonstrated efficacy in managing gout, skillfully regulating serum uric acid (UA) levels and curbing inflammation’s progression. This analysis compiles key foundational research concerning the molecular signaling pathways and UA transporters linked to gout, under the regulation of TCM. The focus includes individual botanical drug, active compounds, and TCM formulations, which have been consolidated and examined in this overview. The primary keywords chosen were “gout, hyperuricemia, gouty arthritis, traditional Chinese medicine, Chinese botanical drug, medicinal botanical drug, and natural plant”. Various relevant literature published within the last 5 years were gathered from electronic databases, including PubMed, Web of Science, CNKI, and others. The findings revealed that TCM has the capacity to modulate various signaling pathways, including MAPK, NF-κB, PI3K/Akt, NLRP3 and JAK/STAT. Additionally, it impacts UA transporters like URAT1, GLUT9, ABCG2, as well as OATs and OCTs, thereby contributing to gout treatment. TCM helps maintain a balanced inflammatory interaction and facilitates UA excretion. This study enhances our understanding of TCM’s anti-gout mechanisms and introduces novel perspectives for establishing the clinical significance and future prospects of TCM-based gout treatment.

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“…The majority of uric acid exists as urate ions at physiological pH (∼7.4), which cannot freely traverse the cellular phospholipid bilayer . Consequently, the reabsorption and secretion of uric acid rely on various urate transporters. , During renal excretion, the primary reabsorption transporters are urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9), which serve as major determinants of SUA levels and of gout development. − …”

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Thienopyrimidine Compound as a Urate Transporter 1 and Glucose Transporter 9 Dual Inhibitor with Improved Efficacy and Favorable Druggability

Shi,

Zhao,

Wang

et al. 2024

J. Med. Chem.

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Gout and hyperuricemia are metabolic diseases characterized with high serum uric acid (SUA) levels that significantly impact human health. Lesinurad, a uricosuric agent, is limited to concurrent use with xanthine oxidase inhibitors (XOIs) in clinical practice due to its restricted efficacy and potential nephrotoxicity. Herein, extensive structural modifications of lesinurad were conducted through scaffold hopping and substituent modification strategies, affording 54 novel derivatives containing pyrimidine-fused cyclic structures. Notably, the thienopyrimidine compound 29 demonstrated a remarkable 2fold increase in SUA-lowering in vivo activity compared to lesinurad, while exhibiting potent inhibitory activity against the urate transporter 1 (URAT1, IC 50 = 2.01 μM) and glucose transporter 9 (GLUT9, IC 50 = 18.21 μM). Furthermore, it possessed a lower effective dosage of 0.5 mg/kg, favorable safety profile without any apparent acute toxicity at doses of 1000 mg/kg, and improved pharmacokinetic properties. Overall, we have discovered an efficacious URAT1/GLUT9 dual inhibitor for inhibiting urate reabsorption with favorable pharmacokinetic profiles.

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Glucose Transporter 9 (GLUT9) Plays an Important Role in the Placental Uric Acid Transport System

Cited by 8 publications

References 24 publications

Hyperuricemia during Pregnancy Leads to a Preeclampsia-Like Phenotype in Mice

Hyperuricemia during Pregnancy Leads to a Preeclampsia-Like Phenotype in Mice

TCM and related active compounds in the treatment of gout: the regulation of signaling pathway and urate transporter

Discovery of a Novel Thienopyrimidine Compound as a Urate Transporter 1 and Glucose Transporter 9 Dual Inhibitor with Improved Efficacy and Favorable Druggability

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