Roles and crosstalks of macrophages in diabetic nephropathy

Abstract

Diabetic nephropathy (DN) is the most common chronic kidney disease. Accumulation of glucose and metabolites activates resident macrophages in kidneys. Resident macrophages play diverse roles on diabetic kidney injuries by releasing cytokines/chemokines, recruiting peripheral monocytes/macrophages, enhancing renal cell injuries (podocytes, mesangial cells, endothelial cells and tubular epithelial cells), and macrophage-myofibroblast transition. The differentiation and cross-talks of macrophages ultimately result renal inflammation and fibrosis in DN. Emerging evidence shows that targeting macrophages by suppressing macrophage activation/transition, and macrophages-cell interactions may be a promising approach to attenuate DN. In the review, we summarized the diverse roles of macrophages and the cross-talks to other cells in DN, and highlighted the therapeutic potentials by targeting macrophages.

Keywords: diabetic nephropathy; fibrosis; inflammation; macrophage; metabolic disorder.

Figure 1

Origins and phenotypes of macrophages. Renal macrophages (Mφ) are consisting of resident macrophages and infiltrating macrophages. Resident macrophages mainly have three sources including yolk sac-derived erythro-myeloid progenitors (EMPs)-derived Mφ, fetal liver EMP-derived Mφ, and hematopoietic stem cell (HSC)-derived Mφ. During the initial stages of kidney injury, resident macrophages act as gatekeepers to initiate or suppress immune responses. Actived resigent Mφ and kidney cells release chemokines/cytokines to recruit circulating monocytes to kidney tissuse (called infiltrating macrophages). Macrophages are generally classified into classic M1 and alternative M2 macrophages. M1 macrophages (CD68/iNOS) express and secrete inflammatory cytokines (TNF-α, IL-1β, IL-6) and promote tissue inflammation. M2 macrophages (CD206/CD163/Arg-1/MR) secrete anti-inflammatory (IL-10) and pro-fibrotic cytokines (TGF-β) that promote tissue repair and fibrosis. Arg-1, Arginase-1; EMPs, Erythro-myeloid progenitors; CCL2, C-C Motif chemokine ligand 2; HSC, Hematopoietic stem cell; ICAM-1, Intercellular adhesion molecule-1; MR, Mannose receptor; Mφ, Macrophages; VCAM-1, Vascular cell adhesion molecule-1; VECs, Vascular endothelial cell.

Figure 2

Cross-talks among macrophages and other cells in DN. Macrophages promote injuries or deaths of renal cells (podocytes, mesangial cells tubular epithelial cells, endothelial cells) by various mechanisms. Mesenchymal setem cells could promote macrophages transdifferentiated into myofibroblast and contribute to tissue fibrosis. A2BAR, A2B adenosine receptor; DR5, Death receptor 5; DN, Diabetic nephropathy;DUSP1, Dual specificity protein phosphatase 1; EV, Extracellular vesicles; HIF-1α, Hypoxia-inducible factor-1α; LRG1, Leucine-rich α-2-glycoprotein 1; MAPK, Mitogen-activated protein kinase; MMT, Macrophage-myofibroblast transition; PGC-1α, Peroxisome proliferator-activated receptor-gamma coactivator-1α; ROS, Reactive oxygen species; SIRT6, Sirtuin-6; TFEB, transcription factor EB; TGFβR1, TGFβ receptor 1; Tim3, T cell immunoglobulin domain and mucin domain-3; TLR4, Toll-like receptor 4; TRAIL, Tumor necrosis factor-related apoptosis-inducing ligand.

Figure 3

Roles of macrophages in DN progression. Macrophages contribute progression of DN via glucotoxicity and lipotoxicity-induced injuries, inflammation and fibrosis in kidney. DN, Diabetic nephropathy; ERK, Extracellular signal-regulated kinase; FTO, Fat mass and obesity-associated; HIF-1α, Hypoxia-inducible factor-1α; HK1, Hexokinase-1; LDHA, Lactate dehydrogenase A; LDL, Low-density lipoprotein; LncRNAs, Long noncoding RNAs; LXRs, Liver X receptors; MMT, Macrophage-myofibroblast transition; MRP8, Myeloid-associated protein 8; PDGF, Platelet-derived growth factor; PFKFB3, 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3; TAB1, Transforming growth factor beta-activated kinase 1-binding protein 1; TAK1, Transforming growth factor beta-activated kinase 1; TLR4, Toll-like receptor 4.