Program Director/Principal Investigator (Last, First, Middle): Pallone, Thomas L. PROJECT SUMMARY (See instructions): The vasa recta of the renal medulla trap NaCI and urea deposited to the interstitium by nephrons and distribute blood flow to the outer and inner medulla. Descending vasa recta (DVR) supply all blood flow to both regions. The cells that comprise the DVR wall (smooth muscle / pericytes and endothelia) regulate vasoactivity through the interactions of ion channels and signaling molecules. DVR endothelia provides both barrier (permeability) function and regulates vasoactivity. The endothelium is """"""""mechanosensitive"""""""" such that increases in luminal flow yield increases in cytoplasmic Ca2+ ([Ca2+]cYr), NO generation and transmural solute permeability. Electrophysiological studies of the DVR endothelium have shown that it is an electrical syncytium in which cells strongly couple to one another via gap junctions. External K+ is a strong regulator gap junction conductance. Strong inward rectifier K+ channel isoforms regulate membrane potential and induce hyperpolarization in response to small elevations of external K+ ion concentration. Thus K+ ion may play a key role in the regulation of perfusion of the renal medulla. We propose to study the function of the DVR endothelium with three Aims.
In Aim 1, hydraulic permeability, vasoactivity, NO generation and [Ca2+]cvT will be quantified as a function of external K+ concentration. The separate roles of K(R and BKca channels to mediate the endothelium dependent relaxing functions and modulation of permeability will be tested. The role of BKCa channels as a putative source of K+ ion will be examined by activating them and blocking their effects with K|R channel inhibition.
In Aim 2, the ability of gap junctions to communicate between endothelia and pericytes will be studied. The spread of current and fluorescent probes between cells will be quantified with electrophysiology and fluorescent imaging. The ability of gap junction blockade with K+ ion, specific peptide and nonspecific chemical inhibitors to prevent conduction of current and fluorescent probe diffusion will be tested. Finally, the ability of gap junctions to conduct both vasodilator and constrictor responses along the DVR axis will be quantified by microvessel perfusion, videomicroscopy and image analysis.
In Aim 3 the mechanosensitivity of DVR endothelium will be explored. The requisite roles for [Ca2+]Cvr elevation and signaling via PI3kinase to facilitate NO generation will be tested. In separate series, effects of Ca2+ entry into the endothelium and signaling via PISkinase to mediate flow dependent increases in permeability will be explored. Independence of permeability modulation from NO will be explored for PI3kinase during NOS blockade.
Descending vasa recta provide all blood flow to the medulla of the kidney, a region vital to regulation of the elimination of salt and water in the urine. The medulla has very low oxygen tension and is vulnerable to injury when blood flow to it decreases. Regulation of contraction and dilation of descending vasa recta is a vital physiological process and is the subject of study in this proposal. PROJECT/
|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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