Peptide transport in the mammary gland: expression and distribution of PEPT2 mRNA and protein

Abstract

The lactating mammary gland utilizes free plasma amino acids as well as those derived by hydrolysis from circulating short-chain peptides for protein synthesis. Apart from the major route of amino acid nitrogen delivery to the gland by the various transporters for free amino acids, it has been suggested that dipeptides may also be taken up in intact form to serve as a source of amino acids. The identification of peptide transporters in the mammary gland may therefore provide new insights into protein metabolism and secretion by the gland. The expression and distribution of the high-affinity type proton-coupled peptide transporter PEPT2 were investigated in rat lactating mammary gland as well as in human epithelial cells derived from breast milk. By use of RT-PCR, PEPT2 mRNA was detected in rat mammary gland extracts and human milk epithelial cells. The expression pattern of PEPT2 mRNA revealed a localization in epithelial cells of ducts and glands by nonisotopic high resolution in situ hybridization. In addition, immunohistochemistry was carried out and showed transporter immunoreactivity in the same epithelial cells of the glands and ducts. In addition, two-electrode voltage clamp recordings using PEPT2-expressing Xenopus laevis oocytes demonstrated positive inward currents induced by selected dipeptides that may play a role in aminonitrogen handling in mammalian mammary gland. Taken together, these data suggest that PEPT2 is expressed in mammary gland epithelia, in which it may contribute to the reuptake of short-chain peptides derived from hydrolysis of milk proteins secreted into the lumen. Whereas PEPT2 also transports a variety of drugs, such as selected β-lactams, angiotensin-converting enzyme inhibitors, and antiviral and anticancer metabolites, their efficient reabsorption via PEPT2 may reduce the burden of xenobiotics in milk.

An update on renal peptide transporters

“…In the lung, PEPT2 is expressed in type II pneumocytes and in the apical membrane of tracheal and bronchial epithelial cells (31). Furthermore, a recent study has shown the localization of PEPT2 in the apical membranes of the epithelial cells of the terminal duct and glandules as well as the main and segmental ducts in the lactating mammary gland (30). By RT-PCR, expression of PEPT2 mRNA was also demonstrated in the spleen, colon, and pancreas (20).…”

“…Although PEPT1 is found in the intestine and in bile duct epithelium (36,47), in these locations it does not contribute to the clearance of diand tripeptides from the circulation. PEPT2 has been localized to the apical membrane of tracheal and bronchial epithelial cells in the lung (31) and ductal cells of the lactating mammary gland (30), but by this localization PEPT2 cannot also play a role in the clearance of short-chain peptides from the blood. Functional studies using isolated choroid plexus suggest that PEPT2 there is located in the apical membrane, where it may mediate the removal of di-and tripeptides from the cerebrospinal fluid to the blood (46) rather then serving as an import system.…”

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

“…Pept2 mRNA is expressed in specific cell types of the brain, including astrocytes, subependymal cells, and ependymal cells, and Pept2 protein is detected along the apical membrane of epithelial cells of the choroid plexus (Table 5) (Berger and Hediger, 1999;Shu et al, 2002). Pept2/PEPT2 mRNA and/or protein are also expressed in the enteric nervous system, colon, liver, pancreas, lungs, nasal mucosa, and mammary glands (Groneberg et al, 2001(Groneberg et al, , 2002Zhang et al, 2004a;Bahadduri et al, 2005;Ruhl et al, 2005;Lu and Klaassen, 2006;Quarcoo et al, 2009).…”

Genetic Variants of the Human H+/Dipeptide Transporter PEPT2: Analysis of Haplotype Functions

“…PEPT2 is present at the apical membrane of choroidal plexus epithelial cells and may function in the efflux of peptides across the blood-brain barrier from cerebrospinal fluid to blood (Shu et al, 2002). In mammary gland epithelia, PEPT2 is thought to be involved in the reuptake of small peptides that accumulate from the hydrolysis of milk proteins (Groneberg et al, 2002). PEPT2 is located in alveolar type II pneumocytes, bronchial epithelium, and endothelium of small vessels (Groneberg et al, 2001) and thought to be responsible for uptake of di-and tripeptides in the lung (Groneberg et al, 2001).…”