Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Medical Imaging, Radboud University Medical Center, Nijmegen, The Netherlands.
Am J Physiol Renal Physiol. 2024 Apr 1;326(4):F622-F634. doi: 10.1152/ajprenal.00239.2023. Epub 2024 Feb 29.
Calciprotein particles (CPPs) provide an efficient mineral buffering system to prevent the complexation of phosphate and calcium in the circulation. However, in chronic kidney disease (CKD), the phosphate load exceeds the mineral buffering capacity, resulting in the formation of crystalline CPP2 particles. CPP2 have been associated with cardiovascular events and mortality. Moreover, CPP2 have been demonstrated to induce calcification in vitro. In this study, we examined the fate of CPP2 in a rat model of CKD. Calcification was induced in Sprague-Dawley rats by 5/6 nephrectomy (5/6-Nx) combined with a high-phosphate diet. Control rats received sham surgery and high-phosphate diet. Twelve weeks after surgery, kidney failure was significantly induced in 5/6-Nx rats as determined by enhanced creatinine and urea plasma levels and abnormal kidney histological architecture. Subsequently, radioactive and fluorescent (FITC)-labeled CPP2 ([Zr]Zr-CPP2-FITC) were injected intravenously to determine clearance in vivo. Using positron emission tomography scans and radioactive biodistribution measurements, it was demonstrated that [Zr]Zr-CPP2-FITC are mainly present in the liver and spleen in both 5/6-Nx and sham rats. Immunohistochemistry showed that [Zr]Zr-CPP2-FITC are predominantly taken up by Kupffer cells and macrophages. However, [Zr]Zr-CPP2-FITC could also be detected in hepatocytes. In the different parts of the aorta and in the blood, low values of [Zr]Zr-CPP2-FITC were detectable, independent of the presence of calcification. CPP2 are cleared rapidly from the circulation by the liver and spleen in a rat model of CKD. In the liver, Kupffer cells, macrophages, and hepatocytes contribute to CPP2 clearance. Calciprotein particles (CPPs) buffer calcium and phosphate in the blood to prevent formation of crystals. In CKD, increased phosphate levels may exceed the buffering capacity of CPPs, resulting in crystalline CPPs that induce calcification. This study demonstrates that labeled CPPs are predominantly cleared from the circulation in the liver by Kupffer cells, macrophages, and hepatocytes. Our results suggest that targeting liver CPP clearance may reduce the burden of crystalline CPP in the development of vascular calcification.
钙磷蛋白颗粒 (CPPs) 提供了一种有效的矿物质缓冲系统，以防止循环中磷酸盐和钙的络合。然而，在慢性肾脏病 (CKD) 中，磷酸盐负荷超过了矿物质缓冲能力，导致结晶 CPP2 颗粒的形成。CPP2 与心血管事件和死亡率有关。此外，CPP2 已被证明可在体外诱导钙化。在这项研究中，我们在 CKD 大鼠模型中研究了 CPP2 的命运。通过 5/6 肾切除术 (5/6-Nx) 联合高磷饮食诱导 Sprague-Dawley 大鼠发生钙化。对照组大鼠接受假手术和高磷饮食。手术后 12 周，通过增强的肌酐和尿素血浆水平以及异常的肾脏组织学结构，显著诱导 5/6-Nx 大鼠发生肾衰竭。随后，静脉注射放射性和荧光 (FITC) 标记的 CPP2 ([Zr]Zr-CPP2-FITC) 以确定体内清除率。通过正电子发射断层扫描和放射性生物分布测量，证明 [Zr]Zr-CPP2-FITC 主要存在于 5/6-Nx 和假手术大鼠的肝脏和脾脏中。免疫组织化学显示，[Zr]Zr-CPP2-FITC 主要被枯否细胞和巨噬细胞摄取。然而，[Zr]Zr-CPP2-FITC 也可在肝细胞中检测到。在主动脉的不同部位和血液中，可检测到低浓度的 [Zr]Zr-CPP2-FITC，与钙化的存在无关。CPP2 在 CKD 大鼠模型中通过肝脏和脾脏从循环中快速清除。在肝脏中，枯否细胞、巨噬细胞和肝细胞有助于 CPP2 的清除。钙磷蛋白颗粒 (CPPs) 缓冲血液中的钙和磷酸盐，以防止晶体形成。在 CKD 中，增加的磷酸盐水平可能超过 CPPs 的缓冲能力，导致诱导钙化的结晶 CPP。本研究表明，标记的 CPPs 主要通过肝脏中的枯否细胞、巨噬细胞和肝细胞从循环中清除。我们的结果表明，靶向肝脏 CPP 清除可能会减少血管钙化发展中结晶 CPP 的负担。
