Regulation of renal amino acid (AA) transport by hormones, drugs and xenobiotics - a review

Fleck, Christian; Schwertfeger, M.; Taylor, Peter M.

doi:10.1007/s00726-002-0316-6

Cited by 29 publications

(16 citation statements)

References 260 publications

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“…Here, aminoaciduria cannot be attributed to impaired renal amino acid reabsorption, because protein amino acid levels were also increased in serum of the volunteers treated with the highest dose of prednisolone at day 1. Moreover, GCs have previously been shown to enhance kidney amino acid reabsorption in rats [22,23]. …”

Section: Discussionmentioning

confidence: 99%

Assessing the metabolic effects of prednisolone in healthy volunteers using urine metabolic profiling

et al. 2012

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BackgroundGlucocorticoids, such as prednisolone, are widely used anti-inflammatory drugs, but therapy is hampered by a broad range of metabolic side effects including skeletal muscle wasting and insulin resistance. Therefore, development of improved synthetic glucocorticoids that display similar efficacy as prednisolone but reduced side effects is an active research area. For efficient development of such new drugs, in vivo biomarkers, which can predict glucocorticoid metabolic side effects in an early stage, are needed. In this study, we aim to provide the first description of the metabolic perturbations induced by acute and therapeutic treatments with prednisolone in humans using urine metabolomics, and to derive potential biomarkers for prednisolone-induced metabolic effects.MethodsA randomized, double blind, placebo-controlled trial consisting of two protocols was conducted in healthy men. In protocol 1, volunteers received placebo (n = 11) or prednisolone (7.5 mg (n = 11), 15 mg (n = 13) or 30 mg (n = 12)) orally once daily for 15 days. In protocol 2, volunteers (n = 6) received placebo at day 0 and 75 mg prednisolone at day 1. We collected 24 h urine and serum samples at baseline (day 0), after a single dose (day 1) and after prolonged treatment (day 15) and obtained mass-spectrometry-based urine and serum metabolic profiles.ResultsAt day 1, high-dose prednisolone treatment increased levels of 13 and 10 proteinogenic amino acids in urine and serum respectively, as well as levels of 3-methylhistidine, providing evidence for an early manifestation of glucocorticoid-induced muscle wasting. Prednisolone treatment also strongly increased urinary carnitine derivatives at day 1 but not at day 15, which might reflect adaptive mechanisms under prolonged treatment. Finally, urinary levels of proteinogenic amino acids at day 1 and of N-methylnicotinamide at day 15 significantly correlated with the homeostatic model assessment of insulin resistance and might represent biomarkers for prednisolone-induced insulin resistance.ConclusionThis study provides evidence that urinary metabolomics represents a noninvasive way of monitoring the effect of glucocorticoids on muscle protein catabolism after a single dose and can derive new biomarkers of glucocorticoid-induced insulin resistance. It might, therefore, help the development of improved synthetic glucocorticoids.Trial RegistrationClinicalTrials.gov NCT00971724

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Section: Discussionmentioning

confidence: 99%

Assessing the metabolic effects of prednisolone in healthy volunteers using urine metabolic profiling

et al. 2012

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“…The investigation of amino acid transport pathways in the renal tubular epithelium has delineated several transport systems [30][31][32]. These systems include various electrogenic and electroneutral, Na + -dependent (concentrative) and Na + -independent, cotransport, antiport, and uniport (facilitated diffusion) systems, for acidic, dibasic, and neutral amino acids, that reside in the luminal or basolateral membrane of proximal tubular cells [30].…”

Section: Discussionmentioning

confidence: 99%

“…Interstitium to lumen oriented backflux through paracellular pathways also occurs. This complex array of amino acid transport pathways is modulated by various intracellular and extracellular, hormonal and nonhormonal, adaptive and regulatory factors [30][31][32]. A derangement in any of these transport systems or regulatory mechanisms can result in aminoaciduria.…”

Section: Discussionmentioning

confidence: 99%

A novel missense mutation in SLC5A2 encoding SGLT2 underlies autosomal-recessive renal glucosuria and aminoaciduria

Magen¹,

Sprecher²,

Zelikovic³

et al. 2005

Kidney International

103

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Our findings confirm that mutations in SLC5A2 result in autosomal-recessive FRG. The severe glucosuria in homozygotes for the K321R mutation highlights the importance of the eighth SGLT2 transmembrane domain for normal glucose transport. We suggest that the generalized aminoaciduria accompanying FRG is a consequence of the severe impairment in glucose reabsorption, and is probably not directly related to the SGLT2 mutation. The exact role of the aberrant glucose transport in the pathogenesis of aminoaciduria remains to be established.

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“…Threo-β-hydroxyaspartate (THA), an inhibitor of the X-AG transporter, is a substrate for cysteine, glutamate, and aspartate. 50 We selected THA as a competitive inhibitor of QD-CYS uptake. Hek 293 and Hep G2 cells were treated with THA (5 mM, 1 h), prior to incubation of QD-CYS (100 nM, 3 h) ( Figure 4B).…”

Section: Articlementioning

confidence: 99%

Short Ligands Affect Modes of QD Uptake and Elimination in Human Cells

et al. 2011

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In order to better understand nanoparticle uptake and elimination mechanisms, we designed a controlled set of small, highly fluorescent quantum dots (QDs) with nearly identical hydrodynamic size (8À10 nm) but with varied short ligand surface functionalization. The properties of functionalized QDs and their modes of uptake and elimination were investigated systematically by asymmetrical flow fieldÀflow fractionation (AF4), confocal fluorescence microscopy, flow cytometry (FACS), and flame atomic absorption (FAA). Using specific inhibitors of cellular uptake and elimination machinery in human embryonic kidney cells (Hek 293) and human hepatocellular carcinoma cells (Hep G2), we showed that QDs of the same size but with different surface properties were predominantly taken up through lipid raft-mediated endocytosis, however, to significantly different extents. The latter observation infers the contribution of additional modes of QD internalization, which include X-AG cysteine transporter for cysteine-functionalized QDs (QD-CYS).We also investigated putative modes of QD elimination and established the contribution of P-glycoprotein (P-gp) transporter in QD efflux. Results from these studies show a strong dependence between the properties of QD-associated small ligands and modes of uptake/elimination in human cells.

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Regulation of renal amino acid (AA) transport by hormones, drugs and xenobiotics - a review

Cited by 29 publications

References 260 publications

Assessing the metabolic effects of prednisolone in healthy volunteers using urine metabolic profiling

Assessing the metabolic effects of prednisolone in healthy volunteers using urine metabolic profiling

A novel missense mutation in SLC5A2 encoding SGLT2 underlies autosomal-recessive renal glucosuria and aminoaciduria

Short Ligands Affect Modes of QD Uptake and Elimination in Human Cells

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