We have investigated the relative contribution of hydrolysis, intact transport and urinary excretion to the renal clearance of
Gly-Sar,
Gly-Sar-Sar, and
Gly-Gly-Sar in fed and starved rats. The results obtained from isolated kidney perfusion studies are summarized as follows: 1) clearance was fastest for
Gly-Gly-Sar and slowest for
Gly-Sar-Sar, 2) urinary excretion of
Gly-Sar-Sar exceeded that of
Gly-Gly-Sar or
Gly-Sar, 3) there was accumulation of products of hydrolysis of
Gly-Gly-Sar in the perfusate but not of
Gly-Sar or
Gly-Sar-Sar, 4) isolated brush-border and basolateral membranes of renal tubular cells lacked hydrolytic activity against
Gly-Sar and
Gly-Sar-Sar but possessed hydrolytic activity against
Gly-Gly-Sar, 5) an excess amount of
Gly-Sar-Sar reduced the rate of clearance of
Gly-Gly-Sar by approximately 40% and significantly increased urinary excretion of this
peptide, 6) the nonfiltering kidney cleared
Gly-Gly-Sar at a rate which was 50% of that of the filtering kidney but did not clear
Gly-Sar, and 7)
starvation for 96 h was without a significant effect on the renal clearance of either
Gly-Sar or
Gly-Sar-Sar but significantly reduced the renal clearance of
Gly-Gly-Sar and the brush-border membrane
hydrolase activity against this
peptide. We conclude that the molecular structure determines the affinity of
oligopeptides for the membrane transport and hydrolytic systems, which, in turn, determines their efficiency for clearance by the kidney.