FGF23 and the regulation of vitamin D-induced immunity in CKD

描述(由申请人提供)：慢性肾脏病(CKD)是一种死亡率很高的衰弱健康问题。慢性肾脏病早期的特点是循环中成纤维细胞生长因子23(FGF23)水平升高，FGF23是磷酸盐稳态和维生素D代谢的关键内分泌调节因子。在CKD患者和肾功能正常的患者中，FGF23升高是一个独立的死亡危险因素，但其潜在的生理机制尚不清楚。众所周知，FGF23可以抑制肾脏合成维生素D的活性形式1，25-二羟基维生素D(1，25(OH)2D)，但其对其他外周组织的影响尚未确定。在体外的初步研究中，我们发现FGF23抑制人单核细胞合成1，25(OH)2D，提示内分泌和免疫系统之间存在一种全新的联系。我们假设CKD患者中FGF23水平的升高通过抑制单核细胞中的维生素D激活系统来抑制抗菌天然免疫反应。已知1，25(OH)2D的局部合成能刺激抗菌蛋白的产生，如长春花素(LL37)，这可能是人类对感染做出反应的关键机制。因此，对于已经缺乏维生素D的CKD患者，免疫细胞暴露于高水平的FGF23将为充分预防感染提供额外的障碍。拟议的项目将把维生素D和FGF23之间的关系描述为人类免疫的积极和消极调节因素。计划中的实验将确定活性1，25(OH)2D或其前体25-羟基维生素D(25OHD)是否可以消除FGF23的抑制作用。通过这种方式，该提案将评估维持CKD患者最佳免疫功能的潜在治疗策略。该项目的进一步创新将通过使用外周血和腹膜单核细胞来提供。通过使用后者，我们的目标是确定维生素D在高感染风险的组织部位作为人类抗菌功能激活剂的作用。总的来说，这些研究将寻求确定FGF23在内分泌和免疫功能之间的一个全新的功能。通过这样做，该项目将有助于阐明一个关键机制，该机制可能解释FGF23在CKD中的病理影响以及成人和儿童透析患者的高死亡率保持不变。

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) is a debilitating health problem with a high rate of mortality. Early stages of CKD are characterized by elevated circulating levels of fibroblast growth factor 23 (FGF23), a key endocrine regulator of phosphate homeostasis and vitamin D metabolism. Elevated FGF23 is an independent risk factor for mortality in CKD patients and individuals with normal renal function but the underlying physiological mechanism for this is unclear. FGF23 is known to suppress renal synthesis of the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D) but its effects on other peripheral tissues have yet to be defined. In preliminary studies in vitro we have shown that FGF23 suppresses synthesis of 1,25(OH)2D by human monocytes, suggesting an entirely novel link between the endocrine and immune systems. We hypothesize that elevated levels of FGF23 in CKD patients act to suppress antibacterial innate immune responses by inhibiting the vitamin D-activation system in monocytes. Local synthesis of 1,25(OH)2D is known to stimulate production of antibacterial proteins such as cathelicidin (LL37), and this may be a pivotal mechanism by which humans respond to infection. Thus for CKD patients who are already vitamin D-insufficient, the exposure of immune cells to high levels of FGF23 will provide an additional impediment to adequate protection against infection. The proposed project will characterize the relationship between vitamin D and FGF23 as positive and negative regulators of human immunity. Planned experiments will determine whether the suppressive effects of FGF23 can be abrogated by active 1,25(OH)2D or its precursor 25-hydroxyvitamin D (25OHD). In this way the proposal will assess potential therapeutic strategies for maintaining optimal immune function in CKD patients. Further innovation in the project will be provided by the use of both peripheral blood and peritoneal monocytes. By using the latter we will aim to define the role of vitamin D as an activator of human antibacterial function at a tissue site where there is high risk of infection. Collectively these studies will seek to identify an entirely novel function for FGF23 at the interface between endocrine and immune function. In doing so, the project will help to shed light on a key mechanism that may explain the pathological impact of FGF23 in CKD and the unchanged high mortality rate in adult and pediatric dialysis patients.