Comparative Study of Desert and Non-desert Rodent Kidneys

BACKGROUND AND SPECIFIC AIMS The study of physiological adaptation and diversity has been a central issue in ecological and evolutionary physiology. For example, the environmental tuning of an organism’s physiology is often hypothesized to be responsible for allowing an organism to adjust to changing biotic and abiotic conditions, through increases in physiological performance. This is well exemplified by desert-dwelling rodents for whom maintaining water homeostasis is a significant challenge. The mammalian kidney has the capability to produce urine that has a much higher osmolality than blood plasma (300 mosm/(kg H2O)). Kangaroo rat (Dipodomys merriami, K-rat), which lives in the deserts of southwestern US, is highly adapted to survive without drinking water and can produce urine as concentrated as ∼6000 mosm/(kg H2O), nearly twice that of the laboratory rat (which we simply call “rat”). Curiously, despite decades of efforts, the means by which the mammalian kidney produces a urine with an osmolality more than 3–4 times above blood plasma remains controversial. The means by which collecting duct tubular fluid is concentrated in the outer medulla is a well-understood process involving active NaCl transport and countercurrent vascular exchange [39, 82]; this produces a concentrating factor of 2–3 in rat. However, the concentrating mechanism of the inner medulla, where the largest concentrating effect is believed to occur, is not well understood: at this time, there is no generally satisfactory and widely-accepted explanation. The most frequently cited explanation for the inner medullary urine concentrating mechanism is the passive hypothesis proposed by Kokko and Rector [23] and by Stephenson [95]. The passive mechanism hypothesis is that sustained diffusive absorption of NaCl from the loops of Henle can be promoted by a favorable concentration gradient that is sustained by diffusive absorption of urea from collecting ducts; the absorption of NaCl from loops, without accompanying water, concentrates other medullary structures, and dilute ascending thin limb fluid provides for mass balance of solute and water that allows the generation of an axial medullary gradient. However, this hypothesis depends on specialized loop-of-Henle transepithelial transport properties that appear to be inconsistent with measured values from perfused tubule experiments: when these experimental values are used in mathematical models (all of which are based on rat), a significant axial osmolality gradient (i.e., an osmolality gradient distributed along cortico-medullary axis) cannot be generated [51, 52, 63, 96, 104]. Other hypotheses have been proposed in the last 20 years; these include the generation of “external” osmolytes [14, 19, 98, 97], and the peristaltic action of the pelvic wall [21, 22, 51, 89]. However, no other hypothesis has gained general acceptance, and, despite a persistent absence of persuasive evidence, the solute-mixing passive mechanism has remained popular, and it is explicit or implicit in many standard textbooks, e.g., Ref. [93]. Owing to the limited success of all current models, we believe that a different approach is warranted. We propose a comparative study of two rodent kidneys that have widely different concentrating capabilities: the K-rat and the Munich-Wistar (MW) rat, two classical models for studies of the concentrating mechanism that are rarely available in a single lab. The fundamental physiological and anatomical differences between desert and non-desert rodent kidneys may hold the key to water homeostasis in extreme water deprivation. We propose to use a series of mathematical models to investigate and compare renal transport and flow dynamics in the K-rat and MW rat. These models will incorporate new findings associated with papillary muscle contractions, with an ultimate goal of producing urine concentrating models that truly captures dynamic changes of spatial complexity and fluid dynamics.