Heterogeneous susceptibility for uraemic media calcification and concomitant inflammation within the arterial tree

Abstract

BackgroundEnd-stage renal disease (ESRD) is strongly associated with arterial calcification of the tunica media, decreased vascular compliance and sudden cardiac death. Here, we analysed the distribution pattern of uraemic media calcification and concomitant inflammation in mice and men.MethodsUraemia was induced in DBA/2 mice with high-phosphate diet. Subsequently, we analysed arterial medial calcification using histology, mass spectrometry, and wire myography. Gene expression was quantified using a whole transcriptome array and quantitative PCR. In a cohort of 36 consecutive patients with CKD stage 4–5, we measured the calcium score of the coronary arteries, the ascending thoracic aorta and the infrarenal abdominal aorta using computed tomography scans.ResultsUraemic DBA/2 mice showed only minor calcifications in thoracic aortas, whereas there was overt media calcification in abdominal aortas. The transcriptional profile and immunohistochemistry revealed induction of Vcam1 expression by vascular smooth muscle cells in uraemic abdominal aortas. Macrophages infiltrated the tunica media of the abdominal aorta. Anti-inflammatory treatment did not improve uraemic media calcification in our animal model. Arterial calcifications in ESRD patients showed a similar distribution pattern in computed tomography scans, with higher calcium scores of the abdominal aorta when compared with the thoracic aorta.ConclusionTaken together, there was a similar heterogeneous pattern of calcification in both mice and humans, where the abdominal aorta was more prone to media calcification when compared with the thoracic aorta. In uraemia, smooth muscle cells of the abdominal aorta showed a phenotypic switch to an inflammatory and osteoblastic phenotype.

A New Murine Model of Chronic Kidney Disease-Mineral and Bone Disorder

“…Nevertheless, increasing ( n ) numbers in echocardiography and further evaluations such as blood pressure measurement are necessary to characterize the cardiac phenotype in detail. In the presented CKD model, we detected media sclerosis predominantly in the abdominal aorta, which is in line with our previous data published in an HPD-induced acute kidney injury mouse model [ 23 ]. Both in CKD patients and in our CKD mouse model, there is a different susceptibility of the ascending aorta and the abdominal aorta to vascular media calcification [ 23 ].…”

“…In the presented CKD model, we detected media sclerosis predominantly in the abdominal aorta, which is in line with our previous data published in an HPD-induced acute kidney injury mouse model [ 23 ]. Both in CKD patients and in our CKD mouse model, there is a different susceptibility of the ascending aorta and the abdominal aorta to vascular media calcification [ 23 ]. The mechanisms for this observational finding remain elusive so far.…”

“…The mechanisms for this observational finding remain elusive so far. It was speculated that due to their different embryonic origin, vascular smooth muscle cells in different parts of the aorta have a different susceptibility to calcification [ 23 , 24 ].…”

Functional and structural changes in aorta of mice divergently selected for basal metabolic rate

“…Before certain experiments, the endothelium was removed by gently rubbing the intima. A successful endothelial denudation was confirmed by the absence of acetylcholineinduced vasorelaxation (Baranowska-Kuczko et al 2016;Kirsch et al 2015).…”

Autophagy Protects From Uremic Vascular Media Calcification

“…Different murine models of CKD mimicking media calcification exist ( 11 ). Recently, we established a new murine model with acute renal failure due to phosphate nephropathy which can be induced in DBA/2 mice subjected to high-phosphate diet (HPD) ( 12 – 14 ). DBA/2 mice have an alternative splice variant of the Abcc6 gene resulting in an increased susceptibility to develop tissue calcification ( 15 ).…”