Microvascular Transport in the Renal Medulla

肾髓质中的微血管运输

• 批准号: 7987443
• 负责人: THOMAS L PALLONE
• 金额: $ 5.65万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-15 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7987443
• 关键词: Acetylcholine; Acids; Albumins; Bathing; Blood flow; Bradykinin; Cells; Chemicals; Communication; Confocal Microscopy; Connexins; Cyclic AMP; Cytoplasm; Deposition; Diffusion; Dilator; Docking; Electric Capacitance; Electrophysiology (science); Endothelial Cells; Endothelium; Excision; Fluo 4; Fluorescein-5-isothiocyanate; Fluorescence; Fluorescent Probes; Gap Junctions; Generations; Giant Cells; Heptanol; Herbimycin; Image; Image Analysis; In Vitro; Injection of therapeutic agent; Injury; Instruction; Ion Channel; Ions; Lasers; Letters; Measures; Mediating; Membrane Potentials; Methods; Modeling; NG-Nitroarginine Methyl Ester; Nephrons; Oxygen measurement, partial pressure, arterial; Peptides; Perfusion; Pericytes; Permeability; Phenylephrine; Physiologic pulse; Physiological Processes; Play; Principal Investigator; Protein Isoforms; Rectum; Regulation; Research Personnel; Resistance; Role; Rupture; Series; Signal Transduction; Signaling Molecule; Smooth Muscle; Sodium Chloride; Source; Study Subject; System; Testing; Urea; Urine; Variant; Vasodilation; Vasodilator Agents; Video Microscopy; Water; base; cell type; extracellular; fluorescein isothiocyanate dextran; inhibitor/antagonist; inward rectifier potassium channel; kidney medulla; lucifer yellow; migration; patch clamp; prevent; programs; response; solute; src-Family Kinases; wortmannin

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. RELEVANCE (See instructions): 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/

项目主管/首席研究员（最后、第一、中）：Pallone, Thomas L。