The inner medullary urinary concentrating mechanism is an important yet poorly understood renal function. The goal of this project is to advance our understanding of the relationships between structural organization and function, including fluxes of inorganic ions, urea, and water, and the urine concentrating mechanism in the mammalian renal medulla. Three-dimensional architecture underscores the paradigm that the inner medullary interstitium is not one single well-mixed compartment. Incomplete knowledge of loop of Henle transepithelial NaCl, urea, and water permeabilities is the single most critical barrier to creating advanced models that explain generation of the IM osmotic gradient and the UCM. The UCM can only be fully understood by taking into consideration three-dimensional structural and functional architecture of the renal IM. Based on the work of others and on our previous work in determining the functional organization and solute and water fluxes, the three following specific aims will be investigated.
Aim 1, determination of water, urea, and NaCl permeabilities of IM loops of Henle from moderately-concentrating rats.
Aim 2, determination of functional architecture of loops of Henle and CDs, vascular networks, and interstitial nodal spaces (INSs) in the IM.
Aim 3, determination of urea, and NaCl permeabilities of loops of Henle from diuretic and antidiuretic rats, and following vasopressin treatment in vivo and in vitro. Experimental approaches will include: 1) production of three-dimensional reconstruction of all IM thin limbs of Henle's loops, CDs, and vasa recta from serial sections, using immunocytochemical markers of physiological function to identify tubule and vessel segments, sites of cellular transport functions, and interstitial compartments and determination of structure-to-structure interactions, and 2) direct measurements, by in vitro microperfusions, of the NaCl, urea, and water permeabilities of specific thin limb segments defined in the reconstructions. Tubule permeabilities will be investigated with and without vasopressin in vitro, and permeabilities will be investigated following water diuresis, antidiuresis, and exposure to vasopressin in vivo.

Public Health Relevance

Extracellular fluid and solute homeostasis is important for maintaining normal cell function throughout the body. The kidney plays a critical role in maintaining fluid and solute homeostasis and the concentrating mechanism is an essential process in accomplishing this role. The major goal of these studies is to more clearly understand the concentrating mechanism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083338-03
Application #
8427364
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Ketchum, Christian J
Project Start
2011-02-01
Project End
2016-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
3
Fiscal Year
2013
Total Cost
$317,980
Indirect Cost
$108,092
Name
University of Arizona
Department
Physiology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Wei, Guojun; Rosen, Seymour; Dantzler, William H et al. (2015) Architecture of the human renal inner medulla and functional implications. Am J Physiol Renal Physiol 309:F627-37
Pannabecker, Thomas L (2015) Aquaporins in desert rodent physiology. Biol Bull 229:120-8
Nawata, C Michele; Dantzler, William H; Pannabecker, Thomas L (2015) Alternative channels for urea in the inner medulla of the rat kidney. Am J Physiol Renal Physiol 309:F916-24
Evans, Kristen K; Nawata, C Michele; Pannabecker, Thomas L (2015) Isolation and perfusion of rat inner medullary vasa recta. Am J Physiol Renal Physiol 309:F300-4
Pannabecker, Thomas L; Layton, Anita T (2014) Targeted delivery of solutes and oxygen in the renal medulla: role of microvessel architecture. Am J Physiol Renal Physiol 307:F649-55
Pannabecker, Thomas L; Beyenbach, Klaus W (2014) Ca2+ and cAMP signaling pathways interact to increase the diuretic effect of serotonin in Malpighian tubules of the kissing bug. Focus on ""Serotonin triggers cAMP- and PKA-1-mediated intracellular calcium waves in Malpighian tubules of Rhodnius prolixus" Am J Physiol Regul Integr Comp Physiol 307:R819-21
Nawata, C Michele; Evans, Kristen K; Dantzler, William H et al. (2014) Transepithelial water and urea permeabilities of isolated perfused Munich-Wistar rat inner medullary thin limbs of Henle's loop. Am J Physiol Renal Physiol 306:F123-9
Gilbert, Rebecca L; Pannabecker, Thomas L (2013) Architecture of interstitial nodal spaces in the rodent renal inner medulla. Am J Physiol Renal Physiol 305:F745-52
Pannabecker, Thomas L (2013) Comparative physiology and architecture associated with the mammalian urine concentrating mechanism: role of inner medullary water and urea transport pathways in the rodent medulla. Am J Physiol Regul Integr Comp Physiol 304:R488-503
Westrick, Kristen Y; Serack, Bradley; Dantzler, William H et al. (2013) Axial compartmentation of descending and ascending thin limbs of Henle's loops. Am J Physiol Renal Physiol 304:F308-16

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