Background Chronic psychological stress (CPS) is associated with increased intestinal epithelial permeability and visceral hyperalgesia. It is unknown whether corticosterone (CORT) plays a role in mediating alterations of epithelial permeability in response to CPS. Methods Male rats were subjected to 1-hour water avoidance (WA) stress or subcutaneous CORT injection daily for 10 consecutive days in the presence or absence of corticoid-receptor antagonist RU-486. The visceromotor response (VMR) to colorectal distension (CRD) was measured. The in situ single-pass intestinal perfusion was used to measure intestinal permeability in jejunum and colon simultaneously. Key Results We observed significant decreases in the levels of glucocorticoid receptor (GR) and tight junction proteins in the colon but not the jejunum in stressed rats. These changes were largely reproduced by serial CORT injections in control rats and were significantly reversed by RU-486. Stressed and CORT-injected rats demonstrated a 3-fold increase in permeability for PEG-400 (MW) in colon but not jejunum and significant increase in VMR to CRD, which was significantly reversed by RU-486. In addition, no differences in permeability to PEG-4,000 and PEG-35,000 were detected between control and WA groups. Conclusions & Inferences Our findings indicate that CPS was associated with region-specific decrease in epithelial tight junction protein levels in the colon, increased colon epithelial permeability to low-molecular weight macromolecules which were largely reproduced by CORT treatment in control rats and prevented by RU-486. These observations implicate a novel, region-specific role for CORT as a mediator of CPS-induced increased permeability to macromolecules across the colon epithelium.

ABSTRACT:The purpose of this study was to evaluate the role, relevance, and regional dependence of peptide transporter (PEPT) 1 expression and function in mouse intestines using the model dipeptide glycylsarcosine (GlySar). After isolating specific intestinal segments, in situ single-pass perfusions were performed in wild-type and Pept1 knockout mice.

The strategic localization of peptide transporter 2 (PEPT2), a proton-coupled oligopeptide transporter, to the apical membrane of epithelial cells in the kidney and choroid plexus suggests that it plays an important role in the disposition of peptides/mimetics in the body. Therefore, the in vivo significance of PEPT2 was investigated in wild-type and PEPT2 null mice following an i.v. bolus dose (0.05 mol/g body weight) of [ 14 C]glycylsarcosine (GlySar). In PEPT2 null mice, the clearance (total and renal) of GlySar was markedly increased (2-fold), resulting in concomitantly lower systemic concentrations. In addition, renal reabsorption was almost abolished, and GlySar was eliminated by glomerular filtration. Of the 46% of GlySar reabsorbed in wild-type mice, PEPT2 accounted for 86% and PEPT1 accounted for 14% of reabsorbed substrate. Analysis of GlySar uptake in kidney sections revealed that PEPT2 was primarily localized in the outer medullary region. Wild-type mice also had greater choroid plexus concentrations of GlySar and a 5-fold greater choroid plexus/cerebrospinal fluid (CSF) ratio as compared with null mice at 60 min. Null mice exhibited a greater CSF/blood ratio at 60 min (0.9 versus 0.2) and area under the curve (AUC) CSF /AUC blood ratio over 60 min (0.45 versus 0.12), indicating that PEPT2 significantly reduces the exposure of GlySar in CSF. Our in vivo results demonstrate that PEPT2 is the predominant peptide transporter in kidney and that it acts as an efflux transporter in choroid plexus. Thus, PEPT2 may have profound effects on the sensitivity and/or toxicity of peptides and peptide-like drugs.

ABSTRACT:The aim of this study was to examine the role of PEPT2, a protoncoupled oligopeptide transporter of the SLC15 family, on the disposition of the antibiotic cefadroxil in the body, particularly the kidney and brain. Pharmacokinetic, tissue distribution, and renal clearance studies were performed in wild-type and PEPT2 null mice after intravenous bolus administration of

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