Regulation of Renal Cortical Adenosine Levels

描述（由申请人提供）：由于肾皮质表达调节肾小球前微血管张力、肾素释放和钠重吸收的高亲和力1型腺苷受体，因此了解腺苷的肾皮质间质水平是如何调节的非常重要。因为我们对肾皮质间质腺苷调节的理解是初步的，所以这个建议的总体目的是进一步加深我们在这方面的知识。胰腺的静脉引流直接流入门静脉循环，这是一种使胰腺激素浓度最大化的解剖学安排，从而使胰腺激素对肝细胞的影响最大化。胰高血糖素是一种分泌到门静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有力的刺激物，并且肝腺苷酸环化酶的激活导致大量环AMP释放到体循环中。我们假设全身性环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递送至肾皮质，并在肾皮质中通过外磷酸二酯酶（将环AMP转化为AMP）和外-5 '-核苷酸酶（将AMP转化为腺苷）的顺序作用代谢为腺苷。在这种观点中，肝脏分泌内分泌激素原（环AMP），其在靶组织（肾皮质间隙）中通过一组特定的酶（外磷酸二酯酶和外-5 '-核苷酸酶）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嘌呤LC/MS离子捕获分析来测试这一创新假设。提出的机制将在体外和体内解决。在体外，我们将确定是否环AMP添加到近曲小管的基底外侧方面被迅速代谢为腺苷的拟议酶。在体内，我们将确定是否适当的演习适当地影响水平的环磷酸腺苷和腺苷在肾皮质间质室的机制，涉及拟议的酶。这项工作可能会确定一个新的途径，胰腺和肝脏调节肾皮质间质水平的腺苷，并可能揭示重要的机制见解的疾病，如肝肾综合征和代谢综合征X。

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.