Energy-Dependent Urea Transports in Mammals and their Functional Consequences.

In lower organisms (bacteria, fungi, yeast), some species that express the enzyme urease take up urea from the surrounding medium as a source of nitrogen, by energy-dependent urea transporters. In contrast, in mammals, urea is an endproduct of nitrogen metabolism, and the energy-dependent urea transports are associated with either the need to excrete nitrogen efficiently, in the case of excess nitrogen intake, or the need to conserve nitrogen and re-use it, in the case of low nitrogen supply.Three different energy-dependent urea transports have been characterized functionally in the mammalian kidney. One responsible for urea secretion in the straight segment of the proximal tubule (proximal straight tubule, PST), another for urea reabsorption in the upper third of the inner medullary collecting duct (IMCD), and one in the very late portion of the IMCD. But intriguingly, up to now, none of the membrane transporters responsible for these transports has been characterized molecularly.This review describes these urea transports functionally and proposes a candidate transporter responsible for urea secretion in the PST. Based on the study of knockout mice, SLC6A18 has been characterized as a glycine transporter, but several previous observations suggest that it may also serve another function. SLC6A18 is very likely a urea/glycine, sodium-dependent antiport. These observations are described in detail.Energy-dependent urea transport is suspected to also take place in two other organs that express facilitated urea transporters; in the testis, urea secretion could initiate a flux of fluid in seminiferous tubules to ensure sperm transport into the lumen; in the bladder, urea secretion could reclaim urea that is at permanent risk of dissipation, due to the large urea concentration difference between urine and blood and the high expression of the facilitated transporter UT-B on the basal membrane of the urothelium.The energy-dependent secretion of urea in the PST has a number of consequences. (1) It allows a better efficiency of urea excretion and thus may prevent some toxicity of urea. (2) It provides a much better understanding of the urine concentrating mechanism. (3) It explains how urea may influence glomerular filtration rate, indirectly.