**Molecular and Cellular Mechanisms that Induce Arterial Calcification by Indoxyl Sulfate and P-Cresyl Sulfate**

### **Britt Opdebeeck, Patrick C. D'Haese \* and Anja Verhulst**

Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, 2000 Antwerpen, Belgium; britt.opdebeeck2@uantwerpen.be (B.O.); anja.verhulst@uantwerpen.be (A.V.) **\*** Correspondence: patrick.dhaese@uantwerpen.be; Tel.: +32-3-265-2599

Received: 18 December 2019; Accepted: 17 January 2020; Published: 19 January 2020

**Abstract:** The protein-bound uremic toxins, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), are considered to be harmful vascular toxins. Arterial media calcification, or the deposition of calcium phosphate crystals in the arteries, contributes significantly to cardiovascular complications, including left ventricular hypertrophy, hypertension, and impaired coronary perfusion in the elderly and patients with chronic kidney disease (CKD) and diabetes. Recently, we reported that both IS and PCS trigger moderate to severe calcification in the aorta and peripheral vessels of CKD rats. This review describes the molecular and cellular mechanisms by which these uremic toxins induce arterial media calcification. A complex interplay between inflammation, coagulation, and lipid metabolism pathways, influenced by epigenetic factors, is crucial in IS/PCS-induced arterial media calcification. High levels of glucose are linked to these events, suggesting that a good balance between glucose and lipid levels might be important. On the cellular level, e ffects on endothelial cells, which act as the primary sensors of circulating pathological triggers, might be as important as those on vascular smooth muscle cells. Endothelial dysfunction, provoked by IS and PCS triggered oxidative stress, may be considered a key event in the onset and development of arterial media calcification. In this review a number of important outstanding questions such as the role of miRNA's, phenotypic switching of both endothelial and vascular smooth muscle cells and new types of programmed cell death in arterial media calcification related to protein-bound uremic toxins are put forward and discussed.

**Keywords:** uremic toxins; arterial calcification; lipid metabolism; inflammation; coagulation; endothelial dysfunction; epigenetics

**Key Contribution:** Indoxyl sulfate and p-cresyl sulfate promote arterial calcification, and this is linked to a complex interplay between inflammation, coagulation, and lipid metabolism pathways.
