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

慢性肾脏疾病(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。我们证明了可溶型血管内皮生长因子受体1(SFlt1)水平在慢性肾脏病患者和5/6肾切除大鼠中均升高。在慢性肾脏病中上调sFlt-1的机制尚不完全清楚。然而，已知sFlt-1的分泌是通过激活血管紧张素II受体(AT1R)和随后在不同类型的细胞中传递钙调神经磷酸酶信号来刺激的。在此背景下，我们提出了以下假设：1)sFlt-1水平升高导致心脏血管生成受损；2)AT1R阻滞剂和/或钙调神经磷酸酶抑制剂(CNI)和/或sFlt1特异性抗体能够使sFlt-1水平正常化；从而3)避免心脏血管丢失。4)此外，AT1R阻滞剂治疗应能避免心脏重构。通过在对照组大鼠中注射sFlt-1，并使用5/6肾切除大鼠模型，我们旨在研究这些假说，并研究AT1R阻滞剂作为CKD心血管疾病治疗策略的可能性。

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.