Targeting proinflammatory cytokines ameliorates calcifying phenotype conversion of vascular progenitors under uremic conditions in vitro

TY - JOUR

T1 - Targeting proinflammatory cytokines ameliorates calcifying phenotype conversion of vascular progenitors under uremic conditions in vitro

AU - Hegner, Björn

AU - Schaub, Theres

AU - Janke, Daniel

AU - Zickler, Daniel

AU - Lange, Claudia

AU - Girndt, Matthias

AU - Jankowski, Joachim

AU - Schindler, Ralf

AU - Dragun, Duska

PY - 2018/8/14

Y1 - 2018/8/14

N2 - Severe vascular calcification develops almost invariably in chronic kidney patients posing a substantial risk to quality of life and survival. This unmet medical need demands identification of novel therapeutic modalities. We aimed to pinpoint components of the uremic microenvironment triggering differentiation of vascular progenitors to calcifying osteoblast-like cells. In an unbiased approach, assessing the individual potency of 63 uremic retention solutes to enhance calcific phenotype conversion of vascular progenitor cells, the pro-inflammatory cytokines IL-1β and TNF-α were identified as the strongest inducers followed by FGF-2, and PTH. Pharmacologic targeting of these molecules alone or in combination additively antagonized pro-calcifying properties of sera from uremic patients. Our findings stress the importance of pro-inflammatory cytokines above other characteristic components of the uremic microenvironment as key mediators of calcifying osteoblastic differentiation in vascular progenitors. Belonging to the group of "middle-sized molecules", they are neither effectively removed by conventional dialysis nor influenced by established supportive therapies. Specific pharmacologic interventions or novel extracorporeal approaches may help preserve regenerative capacity and control vascular calcification due to uremic environment.

AB - Severe vascular calcification develops almost invariably in chronic kidney patients posing a substantial risk to quality of life and survival. This unmet medical need demands identification of novel therapeutic modalities. We aimed to pinpoint components of the uremic microenvironment triggering differentiation of vascular progenitors to calcifying osteoblast-like cells. In an unbiased approach, assessing the individual potency of 63 uremic retention solutes to enhance calcific phenotype conversion of vascular progenitor cells, the pro-inflammatory cytokines IL-1β and TNF-α were identified as the strongest inducers followed by FGF-2, and PTH. Pharmacologic targeting of these molecules alone or in combination additively antagonized pro-calcifying properties of sera from uremic patients. Our findings stress the importance of pro-inflammatory cytokines above other characteristic components of the uremic microenvironment as key mediators of calcifying osteoblastic differentiation in vascular progenitors. Belonging to the group of "middle-sized molecules", they are neither effectively removed by conventional dialysis nor influenced by established supportive therapies. Specific pharmacologic interventions or novel extracorporeal approaches may help preserve regenerative capacity and control vascular calcification due to uremic environment.

KW - Journal Article

U2 - 10.1038/s41598-018-30626-z

DO - 10.1038/s41598-018-30626-z

M3 - SCORING: Journal article

C2 - 30108259

VL - 8

SP - 12087

JO - SCI REP-UK

JF - SCI REP-UK

SN - 2045-2322

IS - 1

ER -