Table 2.
Middle molecular weight substances increased in CKD and examined for causal effects on cardiovascular calcification or associated readouts.
| Effect | Substance | Species | Tissue or Cell Type | Type of Study | Analysis of Calification or Calcification-Associated Process * by |
Reference | Plasma level in CKD | Classified as Uremic Toxin ** | |
|---|---|---|---|---|---|---|---|---|---|
| In vitro | Animal | ||||||||
| INDUCTION | Bone morphogenetic protein (BMP2) |
Bovine | VSMC | V $ | Calcium content Upregulation of CBFA1/RUNX2 |
Chen [42] | ↑ [42] | ||
| Rat | VSMC | V $ | Upregulation of CBFA1/RUNX2, MSX2 and PIT-1 | Rong [43] 1 | |||||
| Fibroblast growth factor 2 (FGF2) | Human | MSC | V $ | ALP activity Alizarin red staining Calcium content Upregulation of CBFA1/RUNX2, OPN and osterix |
Hegner [41] | ↑ [§] | |||
| Interleukin-1β (IL-1β) |
Human | MSC | V $ | ALP activity Alizarin red staining Calcium content Upregulation of CBFA1/RUNX2, OPN and osterix |
Hegner [41] | ↑ [§] | V | ||
| Interleukin-8 (IL-8) |
Human | VSMC | V $ | Alizarin red staining Calcium content Downregulation of OPN |
Bouabdallah [30] | ↑ [44] | |||
| Parathyroid hormone (PTH) |
Human | MSC | V $ | ALP activity Alizarin red staining Calcium content Upregulation of CBFA1/RUNX2, OPN and osterix |
Hegner [41] | ↑ [§] | V | ||
| S100A12 (RAGE ligand) |
Mouse | VSMC | V | Alizarin red staining Increased ROS generation Upregulation of PIT-1, BMP2 and CBFA1/RUNX2 |
Belmokhtar [36] | ↑ [45] | |||
| Salusin-β | Human | VSMC | V & | Calcium content ALP activity Alizarin red staining Increased ROS generation Upregulation of BMP2 and CBFA1/RUNX2 |
Sun [46] | ↑ [47] | |||
| Rat | Aorta | V & | Calcium content ALP activity Von Kossa staining |
Sun [46] | |||||
| Tumor necrosis factor alpha (TNF-α) |
Human | MSC | V | ALP activity Alizarin red staining Calcium content Upregulation of CBFA1/RUNX2, OPN and osterix |
Hegner [41] | ↑ [§] | V | ||
| Human | VSMC | V $ | Calcium content | Guerrero [33] | |||||
| Human | VSMC | V $ | ALP activity | Zickler [48] | |||||
| Human | VSMC | V $ | Calcium content | Zickler [49] | |||||
| Rat | Aorta | V $ | Calcium content | Guerrero [33] | |||||
| Vascular cell adhesion molecule-1 (VCAM-1) | Human | VSMC | V $ | ALP activity Alizarin red staining |
Zickler [48] | ↑ [50] | |||
| NO EFFECT | Soluble tumor necrosis factor receptor-1 (sTNFR-1) |
Human | VSMC | V $ | ALP activity Alizarin red staining |
Zickler [48] | ↑ [48] | ||
| Soluble tumor necrosis factor receptor-2 (sTNFR-2) |
Human | VSMC | V $ | ALP activity Alizarin red staining |
Zickler [48] | ↑ [48] | |||
| Soluble interleukin-2 receptor (sIL-2R) | Human | VSMC | V $ | ALP activity Alizarin red staining |
Zickler [48] | ↑ [48] | |||
ALP—alkaline phosphatase; BMP2—bone morphogenetic protein 2; CBFA1/RUNX2—core-binding factor subunit alpha-1/runt-related transcription factor 2; MSC—mesenchymal stromal cells (as progenitors of VSMC); OPN—osteopontin; PIT-1—sodium Pi co-transporter-1; ROS—reactive oxygen species; VSMC—vascular smooth muscle cells. * Readouts of calcification-associated processes, such as cell signaling and gene/protein expression, are shown in italic. [§] As described in comprehensive uremic toxins reviews [19,20]. ** As described in comprehensive uremic toxins reviews [19,20,21]. $ In pro-calcifying medium. & In pro as well as non-calcifying media; ↑ indicates increased plasma levels in CKD patients. 1 Literature added manually after checking reference lists of included studies or recent reviews.