Gamble's "economy of water" revisited: studies in urea transporter knockout mice.

The Gamble phenomenon (initially described over 70 years ago as "an economy of water in renal function referable to urea") suggested that urea plays a special role in the urinary concentrating mechanism and that the concentrating mechanism depends in some complex way on an interaction between NaCI and urea. In this study, the role of collecting duct urea transporters in the Gamble phenomenon was investigated in wild-type mice and mice in which the inner medulla collecting duct (IMCD) facilitative urea transporters, UT-A1 and UT-A3, had been deleted (UT-A1/3-/- mice). The general features of the Gamble phenomenon were confirmed in wild-type mice, namely 1) the water requirement for the excretion of urea is less than for the excretion of an osmotically equivalent amount of NaCI; and 2) when fed various mixtures of urea and salt in the diet, less water is required for the excretion of the two substances together than the amount of water needed for the excretion of the two substances separately. In UT-A1/3-/- mice both of these elements of the phenomenon were absent, indicating that IMCD urea transporters play a central role in the Gamble phenomenon. A titration study in which wild-type mice were given progressively increasing amounts of urea showed that the ability of the kidney to reabsorb urea was saturable, resulting in osmotic diuresis above excretion rates of ~6,000 µosmol/day. In the same titration experiments, when increasing amounts of NaCl were added to the diet, mice were unable to increase urinary NaCI concentrations to >420 mM, resulting in osmotic diuresis at NaCI excretion rates of -3,500 µosmol/day. Thus both urea and NaCI can induce osmotic diuresis when large amounts are given, supporting the conclusion that the decrease in water excretion with mixtures of urea and NaCl added to the diet (compared with pure NaCI or urea) is due to the separate abilities of urea and NaCI to induce osmotic diuresis, rather than to any specific interaction of urea transport and NaCI transport at an epithelial level. [ABSTRACT FROM AUTHOR]