Adenosine signaling protects the glomerular endothelium

描述(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个常见原因。肾小球内皮细胞依赖足细胞分泌的血管内皮生长因子(VEGF)维持内皮的稳定性和完整性。肾小球内皮细胞血管内皮生长因子信号的缺失会导致内皮细胞增生症，这是一种内皮细胞功能障碍，临床表现为蛋白尿和高血压。这种疾病既见于先兆子痫(由于一种阻止血管内皮生长因子信号转导的可溶性受体)，也见于几种针对血管生成因子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增加母婴并发症，而基于血管生成的癌症治疗的结果是高效抗癌药物的剂量限制性毒性。 细胞外核苷酸，如三磷酸腺苷，以及它们的水解产物腺苷，是决定内皮健康的重要因素。一般来说，细胞外的ATP是促炎和促血栓形成的，而腺苷则可以预防炎症和血栓形成。被称为胞外核苷酸酶的细胞表面酶将细胞外的三磷酸腺苷转化为腺苷，促进血管内皮细胞的稳定环境。我们假设，在血管内皮生长因子缺乏的情况下，通过细胞表面腺苷受体的腺苷信号是保护免受损伤的重要组成部分。 在这项建议的目标1中，我们将确定非选择性腺苷激动剂是否可以逆转血管内皮生长因子缺乏的小鼠的蛋白尿和肾脏损伤。在目标2中，我们将通过使用选择性的腺苷激动剂和拮抗剂来减轻或加重小鼠的肾损伤，从而确定介导腺苷对肾小球内皮保护作用的特异性腺苷受体(A1、A2a、A2b或A3)。 这些研究将有助于确定在血管内皮生长因子缺乏状态下介导肾损伤的途径，并将确定药物治疗的特定靶点。许多腺苷激动剂和拮抗剂已经被开发出来，其中几种正在进行临床试验，因此可以考虑临床应用，而不会在试验室和床边之间有很长的延误。 公共卫生相关性：在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脏损伤的策略。我们的发现可能会减少妊娠的严重并发症，或者允许更有效地进行癌症化疗。

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.