1. bookVolume 1 (2021): Issue 3 (December 2021)
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2719-3500
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30 Jun 2021
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English
access type Open Access

Emerging role of macrophages in diabetic nephropathy

Published Online: 16 May 2022
Volume & Issue: Volume 1 (2021) - Issue 3 (December 2021)
Page range: 93 - 96
Received: 07 Jan 2021
Accepted: 21 Mar 2022
Journal Details
License
Format
Journal
eISSN
2719-3500
First Published
30 Jun 2021
Publication timeframe
4 times per year
Languages
English
Abstract

Increasing evidence shows that diabetic nephropathy is associated with immune disorder. Macrophages are a key immune cell infiltrating the kidney in both patients and experimental animal models of diabetes, and correlate with progressive renal injury under diabetic conditions. Blockade of renal macrophage infiltration by either genetic deletion or pharmacological inhibition has been shown to improve diabetic renal injury, revealing a pathogenic role of macrophages in diabetic nephropathy. Further, studies identify that M1 macrophages are a key player responsible for diabetic renal injury by triggering renal inflammation, while M2 macrophages are highly heterogenous, and may play diverse roles in either initiating the renal repairing process if renal inflammation is resolved, or promoting progressive renal fibrosis via a macrophage-to-myofibroblast transition (MMT) process if renal inflammation is ongoing. Macrophages may also interact with intrinsic kidney cells to mediate renal inflammation or fibrosis directly or indirectly by producing a variety of proinflammatory cytokines/chemokines and growth factors, or by macrophage-derived exosomes. In summary, macrophages are immunologically important in the pathogenesis of diabetic kidney disease and may play a driving role in the progression of diabetic nephropathy. Targeting macrophages may thus be considered as a novel therapy for combatting diabetic nephropathy.

Keywords

Introduction

Diabetic nephropathy is a common and severe complication of diabetes and is a leading cause of end-stage renal disease. Increasing evidence demonstrates that diabetic nephropathy is an immunological disorder involving many immune aspects including macrophages, T cells and subsets, dendritic cells, and others [1, 2, 3]. Pathologically, diabetic nephropathy is characterized by renal inflammation and fibrosis involving both intrinsic kidney cells and the immune system [1, 2, 3]. Many studies have revealed that macrophages are a major inflammatory cell-type infiltrating the kidney in both patients and experimental animal models of diabetic nephropathy [1, 2, 3, 4]. Indeed, macrophage accumulation contributes significantly to the progression of diabetic nephropathy, as evidenced by increasing serum levels of creatinine and interstitial myofibroblast accumulation and fibrosis [4, 5, 6, 7]. These observations provide a strong evidence for the involvement of macrophages in the pathogenesis of diabetic nephropathy. Thus, understanding the role and mechanisms through which macrophages mediate diabetic nephropathy may be a key step towards the development of preventive and therapeutic strategies for combating diabetic kidney disease.

Role of Macrophages in Diabetic Nephropathy

A direct evidence for a role of macrophages in the pathogenesis of diabetic nephropathy comes from a study involving conditional deletion of macrophages from a diabetic mouse model [8]. By using diphtheria toxin (DT) in the CD11b–DT receptor (CD11b-DTR) transgenic mice, macrophages are specifically deleted, and the development of diabetic nephropathy is suppressed as evidenced by an inhibition of macrophage accumulation and the development of albuminuria and renal fibrosis [8]. Further, studies in macrophage scavenger receptor-A deficient mice and in obese db/db mice treated with an anti-c-fms antibody also show that specific inactivation of macrophages inhibits macrophage-dependent renal inflammation and diabetic nephropathy [9, 10]. All these findings reveal a pathogenic role for macrophages in diabetic nephropathy.

Mechanisms of Macrophage-Mediated Diabetic Nephropathy

There are many mechanisms through which macrophages mediate diabetic nephropathy. As illustrated in Figure 1, macrophages can differentiate into different phenotypes or can interact with intrinsic kidney cells to mediate diabetic nephropathy via direct or indirect mechanisms associated with renal inflammation and fibrosis, which is described below.

Figure 1

Mechanisms of macrophage-mediated diabetic nephropathy. Under diabetic conditions, macrophages can be activated to become M1 proinflammatory macrophages that mediate diabetic nephropathy by producing many proinflammatory cytokines, chemokines, and stress molecules. If renal inflammation is resolved, macrophages can again become the M2 phenotype and produce anti-inflammatory cytokines and growth factors that promote the renal repair process. However, ongoing renal inflammation could drive the proinflammatory macrophages undergoing the fibrosing process via MMT, which plays a key role in renal fibrosis. MMT, macrophage-myofibroblast transition.

M1 macrophage activation and renal inflammation in diabetic nephropathy

Macrophages may regulate diabetic kidney disease by altering their phenotypes. It has been well established that M1 macrophages are responsible for triggering renal inflammation [1, 2, 3]. M1 macrophages are recruited into the kidney at an early stage of diabetes and are considered to be pathogenic in diabetic nephropathy, as M1 macrophages are a rich source of proinflammatory cytokine production [10, 11, 12, 13, 14, 15, 16, 17]. Macrophages may mediate diabetic nephropathy by producing a variety of cytokines and chemokines. It has been shown that monocyte chemoattractant protein-1 (MCP-1, a C-C chemokine CCL2) can promote diabetic renal injury via the CCL2/C-C chemokine receptor 2 (CCR2) signaling pathway, as genetic deletion of MCP-1 or CCR2 or pharmacological blockade of CCR2 is able to protect against streptozotocin (STZ)-induced diabetic kidney disease [11, 12, 13, 14]. These findings provide a strong evidence and rationale for the later development of CCR2 inhibition with CCX140-B in patients with type 2 diabetes [13]. It is possible that macrophages can produce an abundance of proinflammatory cytokines to mediate diabetic nephropathy. Macrophage-derived tumor necrosis factor-α (TNF-α) has been shown to play a role in diabetic renal injury as pharmacological blockade or conditional ablation of TNF-α in macrophages can significantly reduce diabetic kidney disease [15]. T cell immunoglobulin domain and mucin domain-3 (Tim-3) have also exhibited a role in regulating macrophage activation during the development of diabetic nephropathy. In both patients and diabetic mouse models, Tim-3 is highly expressed on renal macrophages and positively correlated with renal dysfunction [16]. Mice with Tim-3 deficiency show an inhibition of STZ-induced diabetic nephropathy. However, adoptive transfer of Tim-3-expressing macrophages, but not Tim-3 knockout macrophages, accelerates diabetic renal injury [16], demonstrating a key role for Tim-3 on macrophages-mediated diabetic nephropathy. In contrast, mice with COX-2 deletion in hematopoietic cells or macrophages on CD11b-Cre COX2f/f mice develop severe diabetic kidney injury, demonstrating a protective role for macrophage cyclooxygenase-2 (COX-2) in the development of diabetic nephropathy [17]. Thus, the immunological status and its balance on macrophages may influence macrophage activation and functions, and the clinical outcomes of diabetic nephropathy.

M2 macrophage activation in renal repair or fibrosis in diabetic nephropathy

Increasing evidence shows that M2 macrophages play diverse roles in renal repair or fibrosis [18, 19, 20, 21]. In contrast to M1 macrophages, which initiate the renal inflammation in the early stage of diabetic nephropathy, M2 macrophages become predominant at the later time points of diabetic kidney disease, with diverse roles involving either the repairing process by producing anti-inflammatory cytokines, growth factor and proangiogenic cytokines involved in the wound healing process when renal inflammation is resolved, or renal fibrosis via direct and indirect mechanisms by promoting macrophage-to-myofibroblast transition (MMT) when renal inflammation is ongoing and severe [18, 19, 20, 21]. Indeed, MMT is a major source of renal myofibroblast origin, which contributes to more than 60% of α-smooth muscle actin-expressing myofibroblasts, and is highly correlated with progressive renal fibrosis in a number of chronic kidney diseases and mediated via transforming growth factor-beta (TGF)-β/Smad3 signaling [22, 23, 24]. It has been well established that TGF-β/Smad3 signaling plays a critical role in the pathogenesis of diabetic nephropathy [25]. Thus, macrophage phenotypes that regulate by TGF-β signaling may determine the clinical outcomes of diabetic nephropathy.

Cellular crosstalk between macrophages and intrinsic kidney cells

It has been well documented that macrophages can interact with the intrinsic kidney cells during renal inflammation, fibrosis, or repair process via production of various cytokines, chemoattractive molecules, or growth factors [18, 19, 20, 21]. Recent studies also demonstrated that macrophage-derived extra-cellular vesicles (EVs) or exosomes also play diverse roles in multiple diseases including diabetic nephropathy [26, 27]. Macrophage EVs contain numerous factors such as miRNAs/long non-coding RNAs (lncRNAs), lipids, cytokines, and growth factors that exert immunosuppressive and immune-stimulating effects. It has been shown that macrophage-derived EVs can act as mediators or regulators of cellular crosstalk between the immune system and renal intrinsic cells during disease progression or regression depending on the micro-environments [28]. High glucose-induced macrophage EVs can activate the profibrotic pathway of glomerular mesangial cells via the TGF-β1/Smad3-dependent mechanism both in vivo and in vitro [29]. In contrast, tubular epithelial cell-derived EVs can promote M1 macrophage activation via a microRNAs (miRNA)-19b-3p-dependent mechanism [30]. Interestingly, interleukin-10 (IL-10)-loaded EVs from engineered macrophages are renal protective for acute tubular injury by promoting mitochondrial fitness and M2 macrophage polarization [31]. All these findings support the regulatory role and novel therapeutic potential of macrophage-derived EVs in diabetic nephropathy [32].

Macrophages as a Potential Therapeutic Target for Diabetic Nephropathy

Although treatment for diabetic nephropathy by directly targeting macrophages remains to be elusive b experimentally, increasing evidence shows that targeting macrophage-dependent proinflammatory pathways such as CCL2/CCR2, TNFα, c-fms, macrophage scavenger receptor, Tim-3, and COX-2 have been experimentally reported [9, 10, 11, 12, 13, 14, 15, 16, 17]. It is also highly possible that the recent development of modified macrophage-derived EVs could be a promising approach for the treatment of diabetic nephropathy [26, 27, 28, 29, 30, 31, 32]. However, it should be pointed out that all these studies are limited to animal models and results remain preliminary and experimental. Therefore, ongoing research into the understanding of the molecular mechanisms of macrophage-mediated diabetic nephropathy may be a key step toward the development of an effective therapy for diabetic nephropathy that specifically targets macrophage-dependent pathways.

Figure 1

Mechanisms of macrophage-mediated diabetic nephropathy. Under diabetic conditions, macrophages can be activated to become M1 proinflammatory macrophages that mediate diabetic nephropathy by producing many proinflammatory cytokines, chemokines, and stress molecules. If renal inflammation is resolved, macrophages can again become the M2 phenotype and produce anti-inflammatory cytokines and growth factors that promote the renal repair process. However, ongoing renal inflammation could drive the proinflammatory macrophages undergoing the fibrosing process via MMT, which plays a key role in renal fibrosis. MMT, Macrophage-myofibroblast transition.
Mechanisms of macrophage-mediated diabetic nephropathy. Under diabetic conditions, macrophages can be activated to become M1 proinflammatory macrophages that mediate diabetic nephropathy by producing many proinflammatory cytokines, chemokines, and stress molecules. If renal inflammation is resolved, macrophages can again become the M2 phenotype and produce anti-inflammatory cytokines and growth factors that promote the renal repair process. However, ongoing renal inflammation could drive the proinflammatory macrophages undergoing the fibrosing process via MMT, which plays a key role in renal fibrosis. MMT, Macrophage-myofibroblast transition.

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