Urea Transporters in Health and Disease

Abstract

Urea transporters are a relatively recent discovery in the overall history of kidney physiology. Urea transport proteins were first proposed in the late 1980s when observations of urea permeability could not be explained by paracellular transport or lipid phase diffusion. The first urea transporter was cloned in 1992 and shortly thereafter a family of urea transporters was described. There are two major subgroups of the SLC14A family of urea transporters: Slc14A2 (or UT-A) and SLC14A1 (or UT-B). UT-A1 and UT-A3, which are expressed in the inner medullary collecting duct (IMCD) are crucial to the kidney’s ability to concentrate urine. UT-A2, which is expressed in the thin descending limb is also involved since knock-out of any of these urea transporters results in a urine concentrating defect in mice. The regulation of urea transporter activity in the IMCD involves modification of UT-A1 and UT-A3 through phosphorylation, glycosylation, and ubiquitination, with subsequent effects on the accumulation of urea transporters in the apical plasma membrane. Long-term regulation of the IMCD urea transporters involves changes in protein abundance in response to changes in hydration status, low protein diets, or adrenal steroids. Vasopressin regulates UT-A1 and UT-A3 through PKA. Hypertonicity regulates UT-A1 through PKCα. The UT-B (Slc14A1) urea transporter was originally isolated from erythrocytes. In the kidney, UT-B is expressed primarily in the descending vasa recta. Urea transporters have been studied using animal models of disease including diabetes insipidus, diabetes mellitus, lithium administration, hypertension, and nephrotoxic drug responses. Several genetically engineered mouse models have been developed to study the different urea transporters. Urearetics, which are inhibitors of UT-A and/or UT-B, are being developed and tested as novel diuretic agents.