The microcirculation of the renal medulla traps NaCI and urea deposited to the interstitium by the loops of Henle and collecting ducts. In the past, vasa recta have been conceptualized as simple """"""""U-tube"""""""" diffusive exchangers. Discovery of aquaporin-1 (AQP1) water channels and the UTB urea carrier in descending vasarecta (DVR) endothelia revises our understanding. Solute gradients drive water loss from DVR to the interstitium across AQP1, a process that probably favors high medullary osmolality by shunting water to AVR and secondarily lowering blood flow to the inner medulla. In addition to AQP1, we have determined that a second mercurial insensitive route conducts small solute driven water flux across the DVR wall. The magnitude of transmural solute gradients responsible for driving water flux across the DVR wall is partially determined by DVR diffusive permeability. In turn, diffusive permeability to solute is both flow / shear rate dependent and subject to long term regulation. We propose the following aims: 1) We will test whether the water channel activity of UTB or other pathway(s) conducts the mercurial insensitive nonAQP1 water flux across DVR. We will measure water transport in UTB null DVR in which AQP1 has been disrupted or blocked by mercurials. We will measure the reflection coefficients of the non AQP1 pathway and determine whether, like UTB, water transport isphloretin sensitive. We will test whether nonAQP1 mediated water flux exhibits characteristics consistent with paracellular transport by examining its correlation with diffusive permeability and testing its bradykinin sensitivity. 2) We will test chronic effects on DVR transport in vehicle and vasopressin treated Brattleboro rats and rats subjected to chronic furosemide diuresis. We will test the effect of high angiotensin II states on permeability. 3) We will study the mechanisms responsible for flow dependence of DVR permeability. The effect of NO synthase blockade and NO donation will be tested. The ability of cyclic nucleotides to prevent flow dependent changes will be examined. 4) We will determine whether endothelial intracellular calcium elevations and NO generation accompanies changes in luminal flow / shear, and test whether superoxide generation modulates bioavailable NO. We will measure endothelial membrane potential and determine whether hyperpolarization occurs when DVR endothelia are subject to shear forces. ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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General Medicine B Study Section (GMB)
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Ketchum, Christian J
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University of Maryland Baltimore
Internal Medicine/Medicine
Schools of Medicine
United States
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Pallone, Thomas L (2014) Complex vascular bundles, thick ascending limbs, and aquaporins: wringing out the outer medulla. Am J Physiol Renal Physiol 306:F505-6
Zhang, Zhong; Payne, Kristie; Pallone, Thomas L (2014) Syncytial communication in descending vasa recta includes myoendothelial coupling. Am J Physiol Renal Physiol 307:F41-52
Zhang, Zhong; Lin, Hai; Cao, Chunhua et al. (2014) Descending vasa recta endothelial cells and pericytes form mural syncytia. Am J Physiol Renal Physiol 306:F751-63
Zhang, Zhong; Payne, Kristie; Cao, Chunhua et al. (2013) Mural propagation of descending vasa recta responses to mechanical stimulation. Am J Physiol Renal Physiol 305:F286-94
Khurana, Sandeep; Raina, Hema; Pappas, Valeria et al. (2012) Effects of deoxycholylglycine, a conjugated secondary bile acid, on myogenic tone and agonist-induced contraction in rat resistance arteries. PLoS One 7:e32006
Blaustein, Mordecai P; Leenen, Frans H H; Chen, Ling et al. (2012) How NaCl raises blood pressure: a new paradigm for the pathogenesis of salt-dependent hypertension. Am J Physiol Heart Circ Physiol 302:H1031-49
Khurana, Sandeep; Raufman, Jean-Pierre; Pallone, Thomas L (2011) Bile acids regulate cardiovascular function. Clin Transl Sci 4:210-8
Edwards, Aurelie; Cao, Chunhua; Pallone, Thomas L (2011) Cellular mechanisms underlying nitric oxide-induced vasodilation of descending vasa recta. Am J Physiol Renal Physiol 300:F441-56
Zhang, Zhong; Lin, Hai; Cao, Chunhua et al. (2010) Voltage-gated divalent currents in descending vasa recta pericytes. Am J Physiol Renal Physiol 299:F862-71
Lin, Hai; Pallone, Thomas L; Cao, Chunhua (2010) Murine vasa recta pericyte chloride conductance is controlled by calcium, depolarization, and kinase activity. Am J Physiol Regul Integr Comp Physiol 299:R1317-25

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