Chronic kidney disease (CKD) is a common disease affecting >15% of the US adult population and has cardiovascular mortality10- to 30-folds greater than that in general population. We recently discovered a novel inflammatory monocyte subset the CD40 monocyte (MC) that has strong inflammatory feature and is elevated in CKD patients. We determined CD40+ MC as a novel inflammatory MC subset which is elevated in CKD subjects. Additional preliminary data lead us to hypothesize that CKD and uremic toxins induce CD40+ inflammatory MC differentiation via CD40 ligand induced CD40 expression, DNA hypomethylation on CD40 promoter, and 2) CD40 Inhibition, inflammasome suppression and DNA methylation therapy can reverse CD40+ MC differentiation, vascular inflammation and atherosclerosis. We will test this hypothesis using three connected Aims.
Aim 1 will investigate the effect of CKD on CD40+ MC differentiation and tissue inflammation in human and mouse models of CKD, and in uremic toxin-treated human/mouse PBMC.
Aim 2 will examine molecular mechanism underlying CKD-induced CD40+ MC differentiation.
Aim 3 will test the therapeutic benefit of CD40 blocking, Casp1 inhibition and DNA methylation on CD40+ MC differentiation, atherosclerosis and kidney function in CKD. Accomplishment of the proposed research will lead to the identification of fundamental mechanistic links between CKD and cardiovascular disease, and novel therapeutic targets.
Chronic kidney disease (CKD) is a common disease affecting >15% of the US adult population and has cardiovascular mortality10- to 30-folds greater than that in general population. In our preliminary studies, we discovered a novel inflammatory monocyte subset, CD40+ monocyte, which has strong inflammatory feature and positively correlated with CKD severity in CKD patients. We will examine the contribution and mechanism of CD40 monocyte differentiation in CKD and in CKD-accelerated vascular disease. Success of this study would lead to the discovery of novel knowledge of CKD- cardiovascular disease (CVD) and lead to the development of new therapeutics for the treatment of CKD-related CVD.
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