Soluble Flt-1 in chronic kidney disease: sites of production, regulation and direct effects on heart vascularisation in the rat 5/6 nephrectomy model

慢性肾脏病中的可溶性 Flt-1：大鼠 5/6 肾切除模型中的产生、调节和对心脏血管化的直接影响

• 批准号: 195603990
• 负责人: Professor Dr. Marcus Brand
• 金额: --
• 依托单位: Medizinische Klinik D: Allg. Innere Medizin und Notaufnahme sowie Nieren- und Hochdruckkrankheiten und Rheumatologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/195603990?language=en
• 关键词: Soluble; Flt; chronic; kidney; disease

Chronic kidney disease (CKD) patients are at greater risk of cardiovascular disease, given that renal insufficiency is associated with impaired heart vascularisation. We demonstrated that soluble VEGF receptor 1 (sFlt1) levels, a VEGF antagonist that impairs angiogenesis, are increased in CKD patients as well as in the 5/6 nephrectomised rat. The mechanisms that upregulate sFlt-1 in CKD are not completely understood. However, it is known that secretion of sFlt-1 is stimulated via angiotensin II receptor (AT1R) activation and subsequent calcineurin signalling in different cell types. In this context, we have raised the following hypotheses: 1) increased sFlt-1 levels lead to impaired heart angiogenesis; 2) the AT1R blocker and/or a calcineurin inhibitor (CNI) and/or a specific antibody against sFlt1 are able to normalise sFlt-1 levels; and consequently 3) avoid loss of heart vessels. 4) In addition, AT1R blocker therapy should be able to avoid heart remodelling. By infusion of sFlt-1 in control rats and by using the 5/6 nephrectomised rat model, we aim to investigate these hypotheses and study the possible use of the AT1R blocker as a therapeutic strategy against cardiovascular disease in CKD.

慢性肾脏病（CKD）患者患心血管疾病的风险更大，因为肾功能不全与心脏血管形成受损有关。我们证明，可溶性VEGF受体1（sFlt 1）的水平，VEGF拮抗剂，损害血管生成，增加CKD患者以及在5/6肾切除大鼠。在CKD中上调sFlt-1的机制尚不完全清楚。然而，已知sFlt-1的分泌在不同细胞类型中通过血管紧张素II受体（AT 1 R）活化和随后的钙调磷酸酶信号传导来刺激。在此背景下，我们提出了以下假设：1）增加的sFlt-1水平导致心脏血管生成受损; 2）AT 1 R阻断剂和/或钙调磷酸酶抑制剂（CNI）和/或针对sFlt-1的特异性抗体能够使sFlt-1水平正常化;并且因此3）避免心脏血管损失。4)此外，AT 1 R阻滞剂治疗应能够避免心脏重塑。通过在对照大鼠中输注sFlt-1和通过使用5/6肾切除大鼠模型，我们的目的是调查这些假设，并研究AT 1 R阻滞剂作为CKD中心血管疾病治疗策略的可能用途。