Layton AT. A mathematical model of the urine concentrating mechanism in the rat renal medulla. I. Formulation and base-case results. Am J Physiol Renal Physiol 300: F356 -F371, 2011. First published November 10, 2010 doi:10.1152/ajprenal.00203.2010.-A new, region-based mathematical model of the urine concentrating mechanism of the rat renal medulla was used to investigate the significance of transport and structural properties revealed in anatomic studies. The model simulates preferential interactions among tubules and vessels by representing concentric regions that are centered on a vascular bundle in the outer medulla (OM) and on a collecting duct cluster in the inner medulla (IM). Particularly noteworthy features of this model include highly urea-permeable and water-impermeable segments of the long descending limbs and highly urea-permeable ascending thin limbs. Indeed, this is the first detailed mathematical model of the rat urine concentrating mechanism that represents high long-loop urea permeabilities and that produces a substantial axial osmolality gradient in the IM. That axial osmolality gradient is attributable to the increasing urea concentration gradient. The model equations, which are based on conservation of solutes and water and on standard expressions for transmural transport, were solved to steady state. Model simulations predict that the interstitial NaCl and urea concentrations in adjoining regions differ substantially in the OM but not in the IM. In the OM, active NaCl transport from thick ascending limbs, at rates inferred from the physiological literature, resulted in a concentrating effect such that the intratubular fluid osmolality of the collecting duct increases ϳ2.5 times along the OM. As a result of the separation of urea from NaCl and the subsequent mixing of that urea and NaCl in the interstitium and vasculature of the IM, collecting duct fluid osmolality further increases by a factor of ϳ1.55 along the IM. countercurrent system; NaCl transport; urea transport; kidney DURING PERIODS OF WATER DEPRIVATION, the mammalian urine concentrating mechanism, which is localized in the renal medulla, stabilizes the osmolality of blood plasma by producing a urine that has an osmolality that substantially exceeds that of blood plasma. However, despite decades of sustained experimental and theoretical investigation (24,37,54,58), the nature of the urine concentrating mechanism in the inner medulla (IM) of the mammalian kidney remains controversial.Anatomic studies have revealed a highly structured organization of tubules and vasa recta in the outer medulla (OM) of some mammalian kidneys (2, 29), with tubules and vessels organized concentrically around vascular bundles, tightly packed clusters of parallel vessels, and tubules containing mostly vasa recta. Recent studies of the three-dimensional architecture of the rat IM and expression of membrane proteins associated with fluid and solute transport in nephrons and vasculature have revealed transport and structural properties that likely impact th...