Regulation of Renal Cortical Adenosine Levels

肾皮质腺苷水平的调节

• 批准号: 7191629
• 负责人: EDWIN Kerry JACKSON
• 金额: $ 32.96万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7191629
• 关键词: 5' -Nucleotidase; Address; Adenosine; Adenylate Cyclase; Affinity; Anabolism; Animals; Arginine; Biological Assay; Blood Circulation; Blood capillaries; Classification; Comprehension; Condition; Control Animal; Cyclic AMP; Diffusion; Digestion; Disease; Dose; Drainage procedure; Electrolyte Balance; Electrolytes; Elements; Endocrine; Enzymes; Equilibrium; Face; Glucagon; Goals; Hepatic; Hepatocyte; Hepatorenal Syndrome; Homeostasis; Hormones; Hypertension; In Vitro; Incubated; Indium; Infusion procedures; Inosine; Intestines; Intravenous; Ions; Kidney; Knowledge; Link; Liquid substance; Liver; Liver Cirrhosis; Measures; Metabolic Syndrome X; Metabolism; Methods; Microdialysis; Morphology; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Organism; Pancreas; Pancreatic Hormones; Pathway interactions; Personal Satisfaction; Physiological; Pilot Projects; Plasma; Play; Portal vein structure; Principal Investigator; Process; Production; Protocols documentation; Purinergic P1 Receptors; Purines; Purpose; Rate; Rattus; Regulation; Renal Tissue; Renin; Research Personnel; Role; Sodium; Stimulus; Surface; Syndrome; Testing; Time; Tissues; Vena caval structure; Venous; Western Blotting; Work; absorption; basolateral membrane; biological adaptation to stress; capillary; concept; extracellular; hepatic vein; in vivo; inhibitor/antagonist; innovation; insight; interstitial; intravenous administration; kidney cortex; liquid chromatography mass spectrometry; novel; phosphoric diester hydrolase; purine; research study; response; uptake

DESCRIPTION (provided by applicant): Because the renal cortex expresses high affinity type 1 adenosine receptors that modulate preglomerular microvascular tone, renin release and sodium reabsorption, it is important to understand how renal cortical interstitial levels of adenosine are regulated. Because our comprehension of the regulation of renal cortical interstitial adenosine is rudimentary, the overall purpose of this proposal is to further our knowledge in this regard. The venous drainage of the pancreas empties directly into the portal circulation, an anatomical arrangement that maximizes concentrations, and therefore effects, of pancreatic hormones on hepatocytes. Glucagon is a pancreatic hormone secreted into the portal circulation. Importantly, glucagon is a powerful stimulant of hepatic adenylyl cyclase, and activation of hepatic adenylyl cyclase causes release of large quantities of cyclic AMP into the systemic circulation. We hypothesize that systemic cyclic AMP (secreted from the liver in response to glucagon) is delivered to the renal cortex via the dense peritubular capillary network and is metabolized in the renal cortex to adenosine via the sequential actions of ectophosphodiesterase (converts cyclic AMP to AMP) and ecto-5'-nucleotidase (converts AMP to adenosine). In this view, the liver secretes an endocrine pro-hormone (cyclic AMP) that is metabolized locally in the target tissue (renal cortical interstitial space) to a biologically active hormone (adenosine) via a specific set of enzymes (ecto-phosphodiesterase and ecto-5'-nucleotidase). The specific goal of this proposal is to test this innovative hypothesis using our newly developed and unique LC/MS ion trapping assay for purines. The proposed mechanism will be addressed both in vitro and in vivo. In vitro we will determine whether cyclic AMP added to the basolateral aspect of proximal convoluted tubules is rapidly metabolized to adenosine by the proposed enzymes. In vivo we will determine whether the appropriate maneuvers appropriately influence the levels of cyclic AMP and adenosine in the renal cortical interstitial compartment by a mechanism involving the proposed enzymes. This work may identify a novel pathway by which the pancreas and liver regulate renal cortical interstitial levels of adenosine and may reveal important mechanistic insights into diseases such as the hepatorenal syndrome and the metabolic syndrome X.

描述（由申请人提供）：由于肾皮质表达高亲和力的 1 型腺苷受体，可调节肾小球前微血管张力、肾素释放和钠重吸收，因此了解肾皮质间质腺苷水平如何调节非常重要。由于我们对肾皮质间质腺苷调节的理解还很初级，因此该提案的总体目的是加深我们在这方面的认识。胰腺的静脉引流直接排空到门静脉循环中，这种解剖结构可以最大限度地提高胰腺激素对肝细胞的浓度，从而最大限度地发挥作用。胰高血糖素是一种分泌到门脉循环中的胰腺激素。重要的是，胰高血糖素是肝腺苷酸环化酶的强效刺激剂，肝腺苷酸环化酶的激活导致大量环AMP释放到体循环中。我们假设全身环 AMP（响应胰高血糖素从肝脏分泌）通过致密的管周毛细血管网络输送到肾皮质，并通过外磷酸二酯酶（将环 AMP 转化为 AMP）和外切 5'-核苷酸酶（将 AMP 转化为腺苷）的连续作用在肾皮质中代谢为腺苷。从这个观点来看，肝脏分泌一种内分泌前激素（环AMP），通过一组特定的酶（外切磷酸二酯酶和外切5'-核苷酸酶）在靶组织（肾皮质间隙）局部代谢为生物活性激素（腺苷）。该提案的具体目标是使用我们新开发的独特的 LC/MS 嘌呤离子捕获测定法来测试这一创新假设。所提出的机制将在体外和体内得到解决。在体外，我们将确定添加到近曲小管基底外侧的环AMP是否会被所提出的酶快速代谢为腺苷。在体内，我们将确定适当的操作是否通过涉及所提出的酶的机制适当地影响肾皮质间质室中环AMP和腺苷的水平。这项工作可能会确定胰腺和肝脏调节肾皮质间质腺苷水平的新途径，并可能揭示肝肾综合征和代谢综合征 X 等疾病的重要机制见解。