Urea and Renal Function in the 21st Century

Abstract

Since the turn of the 21st century, gene knockout mice have been created for all major urea transporters that are expressed in the kidney: the collecting duct urea transporters UT-A1 and UT-A3, the descending thin limb isoform UT-A2, and the descending vasa recta isoform UT-B. This article discusses the new insights that the results from studies in these mice have produced in the understanding of the role of urea in the urinary concentrating mechanism and kidney function. Following is a summary of the major findings: (1) Urea accumulation in the inner medullary interstitium depends on rapid transport of urea from the inner medullary collecting duct (IMCD) lumen via UT-A1 and/or UT-A3; (2) as proposed by Robert Berliner and colleagues in the 1950s, the role of IMCD urea transporters in water conservation is to prevent a urea-induced osmotic diuresis; (3) the absence of IMCD urea transport does not prevent the concentration of NaCl in the inner medulla, contrary to what would be predicted from the passive countercurrent multiplier mechanism in the form proposed by Kokko and Rector and Stephenson; (4) deletion of UT-B (vasa recta isoform) has a much greater effect on urinary concentration than deletion of UT-A2 (descending limb isoform), suggesting that the recycling of urea between the vasa recta and the renal tubules quantitatively is less important than classic countercurrent exchange; and (5) urea reabsorption from the IMCD and the process of urea recycling are not important elements of the mechanism of protein-induced increases in GFR. In addition, the clinical relevance of these studies is discussed, and it is suggested that inhibitors that specifically target collecting duct urea transporters have the potential for clinical use as potassium-sparing diuretics that function by creation of urea-dependent osmotic diuresis.

Efficacy of Fenugreek-based bionanocomposite on renal dysfunction and endogenous intoxication in high-calorie diet-induced obesity rat model—comparative study

“…Chronic regulation involves altering protein abundance in response to changes in hydration status, low protein diets, adrenal steroids, sustained diuresis, or antidiuresis [39][40][41]. Secondary-active transport of urea in the rat kidneys is inducible and involves three sodiumdependent urea transporters which are involved into active urea reabsorption in the apical and basolateral membrane of initial part of IMCD, and also in active urea secretion in the apical membrane of terminal IMCD [42][43][44].…”

Toward the optimal clinical use of the fraction excretion of solutes in oliguric azotemia

“…In the collecting duct, UT-A1 and UT-A3 are active, while the isoform UT-A2 is in the pars recta 63 and descending thin limb, and the isoform UT-B in the descending vasa recta (Figure 3). 64 Just as diuretics can interfere with the active transport of NaCl and alter FeNa, drugs or disease entities that interfere with the active transport of urea will alter the FeUrea. Cytokines from experimental sepsis have been shown to down-regulate urea transporters in the presence of endotoxemia from experimental infection.…”

Complex vascular bundles, thick ascending limbs, and aquaporins: wringing out the outer medulla

“…Finally, not to be neglected, urea is transported by UT-A and UT-B carriers (2,10). As with AQP-1, UT-B localizes to DVR endothelia and RBCs.…”