Targeting Macrophages: Therapeutic Approaches in Diabetic Kidney Disease

Abstract

Diabetes is not solely a metabolic disorder but also involves inflammatory processes. The immune response it incites is a primary contributor to damage in target organs. Research indicates that during the initial phases of diabetic nephropathy, macrophages infiltrate the kidneys alongside lymphocytes, initiating a cascade of inflammatory reactions. The interplay between macrophages and other renal cells is pivotal in the advancement of kidney disease within a hyperglycemic milieu. While M1 macrophages react to the inflammatory stimuli induced by elevated glucose levels early in the disease progression, their subsequent transition to M2 macrophages, which possess anti-inflammatory and tissue repair properties, also contributes to fibrosis in the later stages of nephropathy by transforming into myofibroblasts. Comprehending the diverse functions of macrophages in diabetic kidney disease and regulating their activity could offer therapeutic benefits for managing this condition.

Keywords: diabetic kidney disease; macrophage; polarization.

Figure 1

Crosstalk between macrophages and intrarenal non-myeloid cells. Macrophages engage in communication with various non-myeloid cells within the kidney, creating an amplifying loop that contributes to the advancement of kidney disease. The distinct colors of the lines in the illustration represent different instances of this crosstalk. AGE: advanced glycation end-products; ANGII: angiotensin II; CSF-1: macrophage colony-stimulating factor; DLL4: delta-like ligand 4; IL-1: interleukin-1; IL-6: interleukin-6; MCP-1: monocyte chemoattractant protein-1; MINCLE: macrophage-inducible C-type lectin; MRP8: myeloid-related protein 8; NF-κB: nuclear factor-kappa B; NLRP3: pyrin domain-containing protein 3; ROS: reactive oxygen species; Tim-3: T cell immunoglobulin and mucin domain 3; TNF-α: tumor necrosis factor α; Symbol ↑ equal to “increased”; Symbol ↓ equal to “decreased”.

Figure 2

Adverse conditions that hinder the polarization of M2 macrophages within the diabetic microenvironment. DLL4: delta-like ligand 4; DRP-1: dynamin-related protein 1; HMGB1: high-mobility group box 1; MINCLE: macrophage-inducible C-type lectin; PARP1: Poly [ADP-ribose] polymerase 1; PGC-1α: peroxisome proliferator-activated receptor-gamma coactivator; RAC1: ras-related C3 botulinum toxin substrate 1; SIRT: sirtuin; Treg: regulatory T cell; Symbol ↑ equal to “increased”; Symbol ↓ equal to “decreased”.

Figure 3

Utilizing macrophages as a therapeutic approach for the management of diabetic kidney disease. The macrophage-based approaches for managing diabetic kidney disease primarily focus on reducing monocyte recruitment and macrophage activation, facilitating the shift towards the anti-inflammatory M2 subtype, utilizing ex vivo macrophage cell therapy, and inhibiting the transition of macrophages into myofibroblasts. Solid line represents the direction of development, while the dashed line represents the direction to avoid. CCR2: C-C chemokine receptor type 2; TFEB: transcription factor EB; MIF: macrophage migration inhibitory factor; MSC: mesenchymal stem cell; NGAL: neutrophil gelatinase-associated lipocalin; RAS: renin–angiotensin system.