Short-term regulation of organic anion transporters

Duan, Peng; You, Guofeng

doi:10.1016/j.pharmthera.2009.08.002

Cited by 17 publications

(14 citation statements)

References 87 publications

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“…The differences observed in protein expression for Oat1 and Oat3 in this pathology suggest the existence of differential regulating mechanisms in posttranslational levels for these transporters, as previously proposed [7,30,33,35]. The present results suggest that the degradation mechanisms for both Oat1 and Oat3 are impaired but in an opposite sense.…”

Section: Discussionsupporting

confidence: 79%

Renal Expression and Function of Oat1 and Oat3 in Rats with Vascular Calcification

Bulacio¹,

Hazelhoff²,

Torres³

2012

Pharmacology

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Background/Aims: Calcium overload in vascular smooth muscle is a highly pathogenic event, which progresses with advancing age. Old patients are polymedicated, and several pharmacotherapeutic agents circulate in the plasma as organic anions. The organic anion transporters 1 and 3 (Oat1 and Oat3) are present in renal basolateral membranes, which transport organic anions of pharmacological and physiological interest. This study was designed to evaluate the renal expression and function of Oat1 and Oat3 in rats with vascular calcification. Methods: Vascular calcification was induced by administration of a single dose of vitamin D₃ (300,000 UI/ kg b.w., i.m.) to male Wistar rats 10 days before the experiments. Oat1 and Oat3 expression was assessed by immunoblotting, immunohistochemistry and reverse-transcriptase polymerase chain reaction. The renal clearance of p-aminohippurate (PAH, a prototypical organic anion, substrate of Oat1 and Oat3) was measured by conventional clearance techniques. Results: Oat1 and Oat3 protein levels showed an increase in plasma membranes of renal proximal tubules of treated animals, where both transporters are functional. This could explain the increase observed in the renal clearance of PAH in treated rats. Conclusions: These results suggest the relevance of considering the existence of vascular calcification, which is common in ageing, when organic anion drugs are prescribed.

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Section: Discussionsupporting

confidence: 79%

Renal Expression and Function of Oat1 and Oat3 in Rats with Vascular Calcification

Bulacio¹,

Hazelhoff²,

Torres³

2012

Pharmacology

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“…Here oligosaccharyltransferase transfers mannose‐containing oligosaccharides from lipid‐linked precursors on the ER membrane onto suitable asparagine (N) residues in N‐X‐S/T motifs (where X is any residue, S/T is serine or threonine; Aridor, ). Further processing of the glycoconjugate in the trans ‐Golgi removes three terminal glucose residues and one or more mannose residues prior to reglycosylation with N‐acetylglucosamine, galactose, and sialic acid (Duan and You, ). After these editing steps the proteins are packaged for transport to the plasma membrane (Traub and Kornfeld, ; Opat et al, ).…”

Section: Post‐translational Processing Of Slc Transportersmentioning

confidence: 99%

Section: Post‐translational Processing Of Slc Transportersmentioning

confidence: 99%

“…Transporters undergo endocytosis from and recycling back to the plasma membrane (Duan and You, ). Modulation of these processes enables the fine‐tuning of plasma membrane expression in rapid response to a range of exogenous stimuli (Duan and You, ). Internalization of proteins from the plasma membrane occurs by clathrin‐dependent and caveolin‐dependent pathways (Appelqvist et al, ; Figure ).…”

Section: Post‐translational Processing Of Slc Transportersmentioning

confidence: 99%

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Trafficking and other regulatory mechanisms for organic anion transporting polypeptides and organic anion transporters that modulate cellular drug and xenobiotic influx and that are dysregulated in disease

Murray

Zhou

2017

British J Pharmacology

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Organic anion transporters (OATs) and organic anion-transporting polypeptides (OATPs), encoded by a number of solute carrier (SLC)22A and SLC organic anion (SLCO) genes, mediate the absorption and distribution of drugs and other xenobiotics. The regulation of OATs and OATPs is complex, comprising both transcriptional and post-translational mechanisms. Plasma membrane expression is required for cellular substrate influx by OATs/OATPs. Thus, interest in post-translational regulatory processes, including membrane targeting, endocytosis, recycling and degradation of transporter proteins, is increasing because these are critical for plasma membrane expression. After being synthesized, transporters undergo N-glycosylation in the endoplasmic reticulum and Golgi apparatus and are delivered to the plasma membrane by vesicular transport. Their expression at the cell surface is maintained by de novo synthesis and recycling, which occurs after clathrin- and/or caveolin-dependent endocytosis of existing protein. Several studies have shown that phosphorylation by signalling kinases is important for the internalization and recycling processes, although the transporter protein does not appear to be directly phosphorylated. After internalization, transporters that are targeted for degradation undergo ubiquitination, most likely on intracellular loop residues. Epigenetic mechanisms, including methylation of gene regulatory regions and transcription from alternate promoters, are also significant in the regulation of certain SLC22A/SLCO genes. The membrane expression of OATs/OATPs is dysregulated in disease, which affects drug efficacy and detoxification. Several transporters are expressed in the cytoplasmic subcompartment in disease states, which suggests that membrane targeting/internalization/recycling may be impaired. This article focuses on recent developments in OAT and OATP regulation, their dysregulation in disease and the significance for drug therapy.

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“…The results of our study show that, in fact, there is substantial diurnal and long-term biological variation in both plasma concentrations and renal clearances of secreted solutes. The sources of the observed diurnal variation are likely multiple, and may include fluctuations in plasma concentrations due to diurnal or postprandial changes in intestinal absorption of microbial metabolic byproducts, adaptive post-translational modification of organic anion transporters in response to changing metabolic activity (33), or physiologic variation in tubular secretion function in response to hemodynamic fluctuations. Though assays for measurement of secreted solutes have not yet been used in clinical practice, future incorporation of such measurements into clinical decision making must be done with recognition of the observed biologic variability.…”

Section: Discussionmentioning

confidence: 99%

Diurnal and Long-term Variation in Plasma Concentrations and Renal Clearances of Circulating Markers of Kidney Proximal Tubular Secretion

et al. 2017

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Background The renal proximal tubule is essential for removing organic solutes and exogenous medications from the circulation. We evaluated diurnal, prandial, and long-term biological variation of four candidate endogenous markers of proximal tubular secretion. Methods We used liquid chromatography-mass spectrometry to measure plasma and urine concentrations of hippurate (HA), cinnamoylglycine (CMG), indoxyl sulfate (IS), and p-cresol sulfate (PCS) in 25 healthy adults. We measured plasma concentrations of secreted solutes at 13 time points over a 24-hour period, and again after 2 weeks and 14 weeks of follow-up. We further measured 24-hour renal clearances of secreted solutes at baseline, 2 weeks, and 14 weeks. Results Plasma concentrations of secreted solutes varied over the 24-hour baseline period. Diurnal variation was greatest for HA, followed by CMG, IS, and PCS. Plasma concentrations of HA (P=0.002) and IS (P=0.02), but not CMG and PCS, increased significantly following meals. Long-term intra-individual variation (CVI) in plasma concentrations of secreted solutes over 14 weeks varied from 21.8% for IS to 67.3% for PCS, and exceeded that for plasma creatinine (CVI 7.1%). Variation in 24-hour renal clearances was similar among the secreted solutes (CVA+I 33.6% – 47.3%) and was lower using pooled plasma samples from each study visit. Conclusions Plasma concentrations of HA, CMG, IS, and PCS fluctuate within individuals throughout the day and over weeks. Renal clearances of these secreted solutes, which serve as estimates of renal proximal tubule secretion, are also subject to intra-individual biological variation that can be improved by additional plasma measurements.

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Short-term regulation of organic anion transporters

Cited by 17 publications

References 87 publications

Renal Expression and Function of Oat1 and Oat3 in Rats with Vascular Calcification

Renal Expression and Function of Oat1 and Oat3 in Rats with Vascular Calcification

Trafficking and other regulatory mechanisms for organic anion transporting polypeptides and organic anion transporters that modulate cellular drug and xenobiotic influx and that are dysregulated in disease

Diurnal and Long-term Variation in Plasma Concentrations and Renal Clearances of Circulating Markers of Kidney Proximal Tubular Secretion

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