Upregulation of H+-peptide cotransporter PEPT2 in rat remnant kidney

Abstract

The progression of renal damage resulting from reduced nephron mass has been extensively studied in the 5/6 nephrectomized rat. However, reabsorption of small peptides and D-glucose across the renal proximal tubule in this model remains poorly understood. In this study, we examined the alterations of H(+)-peptide cotransporters (PEPT1 and PEPT2) and Na(+)-D-glucose cotransporters (SGLT1 and SGLT2) in chronic renal failure. Two weeks after surgery, H(+)-dependent [(14)C]glycylsarcosine uptake by the renal brush-border membrane vesicles isolated from 5/6 nephrectomized rats was significantly increased compared with that from sham-operated controls. Kinetic analysis revealed that the maximum velocity value for [(14)C]glycylsarcosine uptake by the high-affinity-type of peptide transporter was increased threefold by 5/6 nephrectomy, without significant changes in the apparent Michaelis-Menten constant value. Competitive PCR analyses indicated that the expression of PEPT2 mRNA was markedly increased in the remnant kidney, but PEPT1, SGLT1, and SGLT2 mRNA levels showed no significant changes. These findings indicated that the high-affinity-type H(+)-peptide cotransport activity is upregulated by 5/6 nephrectomy, accompanied by the increased expression of PEPT2. The upregulation of PEPT2 expression would result in an increase in reabsorption of small peptides and peptide-like drugs across the brush-border membranes in chronic renal failure.