Myeloid CCR2 Promotes Atherosclerosis after AKI

Abstract

Background: The risk of cardiovascular events rises after acute kidney injury. Leukocytes promote atherosclerotic plaque growth and instability. We have established a model of enhanced remote atherosclerosis after renal ischemia reperfusion (IR) injury and investigate the underlying inflammatory mechanisms. Methods: Atherosclerotic lesions and inflammation were investigated in native and bone marrow-transplanted LDL receptor-deficient (LDLr-/-) mice after unilateral renal IR injury using histology, flow cytometry, and gene expression analysis. Results: Aortic root atherosclerotic lesions were significantly larger after renal IR injury than in controls. A gene expression screen revealed enrichment for chemokines and their cognate receptors in aortas of IR-injured mice in early atherosclerosis, and of T cell-associated genes in advanced disease . Confocal microscopy revealed increased aortic macrophage proximity to T cells. Differential aortic inflammatory gene regulation in IR-injured mice largely paralleled the pattern in the injured kidney. Single-cell analysis identified renal cell types that produced soluble mediators upregulated in the atherosclerotic aorta. The analysis revealed a marked early increase in Ccl2, which CCR2+ myeloid cells mainly expressed. CCR2 mediated myeloid cell homing to the post-ischemic kidney in a cell-individual manner. Reconstitution with Ccr2-/- bone marrow dampened renal post-ischemic inflammation, reduced aortic Ccl2 and inflammatory macrophage marker CD11c, and abrogated excess aortic atherosclerotic plaque formation after renal IR. Conclusions: Our data introduce an experimental model of remote proatherogenic effects of renal IR and delineate myeloid CCR2 signaling as a mechanistic requirement. Monocytes should be considered as mobile mediators when addressing systemic vascular sequelae of kidney injury.

Identification of novel prognostic targets in coronary artery disease and related complications using bioinformatics and next generation sequencing data analysis

“…Signaling pathways include immune system [54], metabolism of lipids [55], phospholipid metabolism [56] and disease [57] plays an important role in CAD. DOCK4 [58], CEACAM1 [59], STAT1 [60], ARG1 [61], TLR4 [62], ADAM9 [63], VNN1 [64], ABCA1 [65], STAT2 [66], TLR5 [67], PTGS2 [68], RNF213 [69], ZDHHC17 [70], JAK2 [71], TLR8 [72], NOTCH2 [73], PDGFC (platelet derived growth factor C) [74], CMPK2 [75], TLR2 [76], CYP1B1 [77], CCR1 [78], HDAC9 [79], IL1RN [80], GCH1 [81], LYST (lysosomal trafficking regulator) [82], PELI1 [83], EGR1 [84], SNX10 [85], CA2 [86], ZEB2 [87], HIF1A [88], PLA2G7 [89], CCR2 [90], GAB1 [91], IRAK3 [92], LDLR (low density lipoprotein receptor) [93], TLR6 [94], SIRT1 [95], NOD2 [96], ATP10D [97], ELOVL6 [98], VCAN (versican) [99], TET2 [100], TET3 [101], ZBTB20 [102], HS3ST1 [103], PF4 [104], DNAJC2 [105], NFIA (nuclear factor I A) [106], CCR7 [107], PRDX2 [108], ADK (adenosine kinase) [109], TCF7 [110], LGALS3 [111], OLFM2 [112], HDAC11 [113] and ARPC1B [114] are significantly related to the atherosclerosis. Studies have revealed that KCNJ2 [115], TLR4 [116], JAK2 [117], TLR2 [118], EGR1 [119], GAB1 [120], ZBTB11 [121], BIN1 [122], TCF4 [123], PPP1R13L [124], TRPM4 [125], LGALS3 [126] and SNTA1 [127] plays a key role in cardiac arrhythmia.…”

Role of MCP-1/CCR2 axis in renal fibrosis: Mechanisms and therapeutic targeting

“…[36] MCP-1 and CCR2 are significantly increased in damaged kidneys. [37][38][39][40] After kidney injury, MCP-1 is highly expressed, recruiting and activating monocyte-macrophages to the injury site, and specifically binds to the receptor CCR2 on monocyte-macrophages and exerts biological effects through the calcium-dependent protein kinase C-mediated signaling pathway. Inhibition of MCP-1/CCR2 axis can reduce the infiltration of macrophages into kidneys, thereby reducing inflammation and renal fibrosis in the damaged kidneys.…”

Probing the Association between Acute Kidney Injury and Cardiovascular Outcomes

“…Animal models of AKI have demonstrated cardiac alterations and endothelial dysfunction as distant effects of AKI. 13,14 In humans, AKI has been associated with increases in selected inflammatory cytokines, 15–17 which may increase the risk of subsequent cardiovascular disease analogous to other acute illnesses characterized by inflammation ( e.g. , serious infections).…”

“…Animal models of AKI have demonstrated cardiac alterations and endothelial dysfunction as distant effects of AKI. 13,14 In humans, AKI has been associated with increases in selected inflammatory cytokines, [15][16][17] which may increase the risk of subsequent cardiovascular disease analogous to other acute illnesses characterized by inflammation (e.g., serious infections). 18,19 However, the associations between AKI and cardiovascular disease and death seen in epidemiologic studies may be due to confounding by differences in patient characteristics between patients with and without AKI.…”