The urea transporter UT-A1 plays a predominant role in a urea-dependent urine-concentrating mechanism

Urea transporters are a family of urea-selective channel proteins expressed in multiple tissues that play an important role in the urine-concentrating mechanism of the mammalian kidney. Previous studies have shown that knockout of urea transporter (UT)-B, UT-A1/A3, or all UTs leads to urea-selective diuresis, indicating that urea transporters have important roles in urine concentration. Here, we sought to determine the role of UT-A1 in the urine-concentrating mechanism in a newly developed UT-A1–knockout mouse model. Phenotypically, daily urine output in UT-A1–knockout mice was nearly 3-fold that of WT mice and 82% of all-UT–knockout mice, and the UT-A1–knockout mice had significantly lower urine osmolality than WT mice. After 24-h water restriction, acute urea loading, or high-protein (40%) intake, UT-A1–knockout mice were unable to increase urine-concentrating ability. Compared with all-UT–knockout mice, the UT-A1–knockout mice exhibited similarly elevated daily urine output and decreased urine osmolality, indicating impaired urea-selective urine concentration. Our experimental findings reveal that UT-A1 has a predominant role in urea-dependent urine-concentrating mechanisms, suggesting that UT-A1 represents a promising diuretic target.

A mathematical model of the rat kidney: K+-induced natriuresis

A model of the rat nephron (Weinstein. Am J Physiol Renal Physiol 308: F1098–F1118, 2015) has been extended with addition of medullary vasculature. Blood vessels contain solutes from the nephron model, plus additional species from the model of Atherton et al. ( Am J Physiol Renal Fluid Electrolyte Physiol 247: F61–F72, 1984), representing hemoglobin buffering. In contrast to prior models of the urine-concentrating mechanism, reflection coefficients for DVR are near zero. Model unknowns are initial proximal tubule pressures and flows, connecting tubule pressure, and medullary interstitial pressures and concentrations. The model predicts outer medullary (OM) interstitial gradients for Na+, K+, CO2, and [Formula: see text], such that at OM-IM junction, the respective concentrations relative to plasma are 1.2, 3.0, 2.7, and 8.0; within IM, there is high urea and low [Formula: see text], with concentration ratios of 11 and 0.5 near the papillary tip. Quantitative similarities are noted between K+and urea handling (medullary delivery and permeabilities). The model K+gradient is physiologic, and the urea gradient is steeper due to restriction of urea permeability to distal collecting duct. Nevertheless, the predicted urea gradient is less than expected, suggesting reconsideration of proposals of an unrecognized reabsorptive urea flux. When plasma K+is increased from 5.0 to 5.5 mM, Na+and K+excretion increase 2.3- and 1.3-fold, respectively. The natriuresis derives from a 3.3% decrease in proximal Na+reabsorption and occurs despite delivery-driven increases in Na+reabsorption in distal segments; kaliuresis derives from a 30% increase in connecting tubule Na+delivery. Thus this model favors the importance of proximal over distal events in K+-induced diuresis.

A Novel Approach for Compensating the Significance of Tubule’s Architecture in Urine Concentrating Mechanism of Renal Medulla

Many theories and mathematical simulations have been proposed concerning urine concentrating mechanism (UCM). The WKM and region approach are the two most valuable methods for compensating the effect of tubule’s architecture in renal medulla. They both have tried to simulate tubule’s confinement within a particular region mathematically in one spatial dimension. In this study, continuity, momentum and species transport equations along with standard expressions for transtubular solutes and water transports on tubule’s membrane were solved numerically in three spatial dimensions which practically is the main significance of our novel approach. Model structure has been chosen as simple as possible to minimize the effect of other factors in tubule’s solute and water exchange. It has been tried to simulate the preferential interaction between tubules by introducing different diffusion coefficients for solutes in the intermediate media in order that changing this physical parameter directly could influence tubule’s confinement with respect to each other. The results have been discussed in detail and then the effect of solute’s diffusivity on UCM has been investigated subsequently. In overall, it has been found out that this simulation can validate the integrity of our proposed approach for further investigation in this field.

Comparative physiology and architecture associated with the mammalian urine concentrating mechanism: role of inner medullary water and urea transport pathways in the rodent medulla

Comparative studies of renal structure and function have potential to provide insights into the urine-concentrating mechanism of the mammalian kidney. This review focuses on the tubular transport pathways for water and urea that play key roles in fluid and solute movements between various compartments of the rodent renal inner medulla. Information on aquaporin water channel and urea transporter expression has increased our understanding of functional segmentation of medullary thin limbs of Henle's loops, collecting ducts, and vasa recta. A more complete understanding of membrane transporters and medullary architecture has identified new and potentially significant interactions between these structures and the interstitium. These interactions are now being introduced into our concept of how the inner medullary urine-concentrating mechanism works. A variety of regulatory pathways lead directly or indirectly to variable patterns of fluid and solute movements among the interstitial and tissue compartments. Animals with the ability to produce highly concentrated urine, such as desert species, are considered to exemplify tubular structure and function that optimize urine concentration. These species may provide unique insights into the urine-concentrating process. 1