Adenosine signaling protects the glomerular endothelium

腺苷信号传导保护肾小球内皮

• 批准号: 7875001
• 负责人: David J Friedman
• 金额: $ 8.7万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7875001
• 关键词: Adenosine; Adenosine A1 Receptor; Adverse effects; Affect; Agonist; Albuminuria; Angiogenesis Inhibitors; Antibodies; Antineoplastic Agents; Binding; Cancer Patient; Cell surface; Chemotherapy-Oncologic Procedure; Clinical; Clinical Trials; Complication; Data; Defect; Disease; Dose-Limiting; Endothelial Cells; Endothelium; Enzymes; Fetus; Functional disorder; Future; Goals; Growth Factor; Health; Hydrolysis; Hypertension; Inflammation; Inflammatory; Injury; Kidney; Knockout Mice; Lead; Link; Malignant Neoplasms; Maps; Mediating; Molecular; Mus; Nitric Oxide; Nucleotides; Pathway interactions; Patients; Pharmacotherapy; Placenta; Pre-Eclampsia; Predisposition; Pregnancy; Pregnancy Complications; Prevention; Production; Proteinuria; Purinergic P1 Receptors; Regimen; Renal carcinoma; Resistance; Signal Transduction; Supportive care; Testing; Thrombosis; Time; Toxic effect; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Vascular Endothelium; Wild Type Mouse; Work; adenosine receptor activation; angiogenesis; antiangiogenesis therapy; base; bench to bedside; cancer therapy; cancer type; clinical application; extracellular; fetal; glomerular endothelium; inhibitor/antagonist; injured; mouse model; overexpression; podocyte; prevent; protective effect; public health relevance; receptor; response; tumor

DESCRIPTION (provided by applicant): Preeclampsia and angiogenesis inhibitors used to treat cancer are two common causes of severe glomerular endothelial injury. The glomerular endothelium depends on vascular endothelial growth factor (VEGF) made by podocytes to maintain endothelial stability and integrity. A deficiency of VEGF signaling at the glomerular endothelium causes endotheliosis, a dysfunction of endothelial cells manifested clinically by proteinuria and hypertension. This disorder is seen in both preeclampsia (due to a soluble receptor that blocks VEGF signaling) and as a complication of cancer treatment with several angiogenesis inhibitors directed against VEGF. The clinical consequences in preeclampsia include increased maternal and fetal complications, while with angiogenesis-based cancer treatment the consequence is dose-limiting toxicity for highly effective anti-cancer drugs. Extracellular nucleotides such as ATP, as well as their hydrolysis product adenosine, are important factors in determining the health of the endothelium. In general, extracellular ATP is pro-inflammatory and pro-thrombotic, while adenosine protects against inflammation and thrombosis. Cell surface enzymes called ectonucleotidases convert extracellular ATP to adenosine, promoting a stable milieu for the vascular endothelium. We hypothesize that adenosine signaling via cell surface adenosine receptors is an important component of protection from injury in settings of VEGF deficiency. In aim 1 of this proposal, we will determine if a non-selective adenosine agonist can reverse albuminuria and renal injury in mice with VEGF deficiency. In aim 2, we will identify the specific adenosine receptor (A1, A2a, A2b, or A3) that mediates the protective effect of adenosine on the glomerular endothelium by using selective adenosine agonists and antagonists to ameliorate or accentuate renal injury in our mouse model. These studies will help define pathways that mediate renal injury in states of VEGF deficiency, and will also identify specific targets for drug therapy. A wide range of adenosine agonists and antagonists have already been developed, with several in clinical trials, so that clinical applications could be considered without a long delay between bench and bedside. PUBLIC HEALTH RELEVANCE: In diseases such as pre-eclampsia or complications of some cancer therapies, the kidney is injured by lack of important growth factors. We are developing strategies that might allow prevention or reversal of this kidney injury. Our findings may reduce severe complications of pregnancy or allow for more effective delivery of cancer chemotherapy.

描述（由申请人提供）：先兆子痫和用于治疗癌症的血管生成抑制剂是严重肾小球内皮损伤的两种常见原因。肾小球内皮依赖于足细胞产生的血管内皮生长因子（VEGF）来维持内皮的稳定性和完整性。血管内皮生长因子信号传导在肾小球内皮的缺陷引起内皮增生，一种临床上表现为蛋白尿和高血压的内皮细胞功能障碍。这种疾病见于先兆子痫（由于阻断VEGF信号传导的可溶性受体）和用几种针对VEGF的血管生成抑制剂治疗癌症的并发症。先兆子痫的临床后果包括母体和胎儿并发症增加，而基于血管生成的癌症治疗的后果是高效抗癌药物的剂量限制性毒性。 细胞外核苷酸如ATP及其水解产物腺苷是决定内皮健康的重要因素。一般来说，细胞外ATP是促炎和促血栓形成的，而腺苷则可防止炎症和血栓形成。细胞表面酶称为外核苷酸酶，将细胞外ATP转化为腺苷，促进血管内皮的稳定环境。我们假设，腺苷信号通过细胞表面腺苷受体是一个重要的组成部分，保护从VEGF缺乏的设置中的损伤。 在本提案的目标1中，我们将确定非选择性腺苷激动剂是否可以逆转VEGF缺乏小鼠的蛋白尿和肾损伤。在目标2中，我们将确定特定的腺苷受体（A1，A2a，A2b，或A3）介导的保护作用，腺苷对肾小球内皮细胞通过使用选择性腺苷激动剂和拮抗剂，以改善或加重肾损伤，在我们的小鼠模型。 这些研究将有助于确定在VEGF缺乏状态下介导肾损伤的途径，也将确定药物治疗的特定靶点。已经开发了广泛的腺苷激动剂和拮抗剂，其中几种处于临床试验中，因此可以考虑临床应用，而不会在实验室和床边之间出现长时间的延迟。 公共卫生关系：在诸如先兆子痫或某些癌症治疗的并发症等疾病中，肾脏因缺乏重要的生长因子而受损。我们正在开发可能预防或逆转这种肾损伤的策略。我们的研究结果可能会减少严重的妊娠并发症或允许更有效地提供癌症化疗。