Feenstra Lian, Reijrink Melanie, Pasch Andreas, Smith Edward R, Visser Lotte M, Bulthuis Marian, Lodewijk Monique E, Mastik Mirjam F, Greuter Marcel J W, Slart Riemer H J A, Mulder Douwe J, Pol Robert A, Te Velde-Keyzer Charlotte A, Krenning Guido, Hillebrands Jan-Luuk
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
Department of Internal Medicine, Division of Vascular Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Cardiovasc Res. 2024 Dec 4;120(15):1953-1966. doi: 10.1093/cvr/cvae164.
Calciprotein particles (CPPs) are circulating calcium and phosphate nanoparticles associated with the development of vascular calcification (VC) in chronic kidney disease (CKD). Although recent studies have been focusing on associations of CPPs with the presence of VC in CKD, insights in the underlying processes and mechanisms by which CPPs might aggravate VC and vascular dysfunction in vivo are currently lacking. Here, we assessed the overall burden of abdominal VC in healthy kidney donors and CKD patients and subsequently performed transcriptome profiling in the vascular tissue obtained from these subjects, linking outcome to CPP counts and calcification propensity.
Calcification scores were quantified in renal arteries, iliac arteries, and abdominal aorta using computed tomography (CT) scans of kidney donors and CKD patients. The vascular tissue was collected from kidney donors (renal artery) and CKD patients (iliac artery), after which bulk RNA sequencing and gene set enrichment analysis (GSEA) were performed on a subset of patients. Calcification propensity (crystallization time, T50) was measured using nephelometry and CPP counts with microparticle flow cytometric analysis. Increased calcification scores (based on CT) were found in CKD patients compared to kidney donors. Transcriptome profiling revealed enrichment for processes related to endothelial activation, inflammation, extracellular matrix (ECM) remodelling, and ossification in CKD vascular biopsies compared to kidney donors. Calcification propensity was increased in CKD, as well as CPP counts, with the latter being significantly associated with markers of vascular remodelling.
Our findings reveal that CKD is characterized by systemic VC with increased calcification propensity and CPP counts. Transcriptome profiling showed altered vascular gene expression with enrichment for endothelial activation, inflammation, ECM remodelling, and ossification. Moreover, we demonstrate, for the first time, that vascular remodelling processes are associated with increased circulating CPP counts. Interventions targeting CPPs are promising avenues for alleviating vascular remodelling and VC in CKD.
钙蛋白颗粒（CPPs）是循环中的钙和磷酸盐纳米颗粒，与慢性肾脏病（CKD）中血管钙化（VC）的发生发展相关。尽管最近的研究一直聚焦于CPPs与CKD中VC存在情况的关联，但目前仍缺乏对CPPs在体内可能加重VC和血管功能障碍的潜在过程和机制的深入了解。在此，我们评估了健康肾供体和CKD患者腹部VC的总体负担，随后对从这些受试者获取的血管组织进行转录组分析，将结果与CPP计数和钙化倾向联系起来。
使用肾供体和CKD患者的计算机断层扫描（CT）对肾动脉、髂动脉和腹主动脉的钙化评分进行定量。从肾供体（肾动脉）和CKD患者（髂动脉）收集血管组织，之后对部分患者进行了批量RNA测序和基因集富集分析（GSEA）。使用比浊法测量钙化倾向（结晶时间，T50），并通过微粒流式细胞术分析CPP计数。与肾供体相比，CKD患者的钙化评分（基于CT）增加。转录组分析显示，与肾供体相比，CKD血管活检中与内皮激活、炎症、细胞外基质（ECM）重塑和骨化相关的过程富集。CKD患者的钙化倾向增加，CPP计数也增加，后者与血管重塑标志物显著相关。
我们的研究结果表明，CKD的特征是全身性VC，钙化倾向和CPP计数增加。转录组分析显示血管基因表达改变，内皮激活、炎症、ECM重塑和骨化过程富集。此外，我们首次证明血管重塑过程与循环CPP计数增加有关。针对CPPs的干预措施是减轻CKD中血管重塑和VC的有前景的途径。
