Although macrophages were initially thought to arise predominantly from hematopoietic sources, this notion has been challenged over recent decades (6). Current evidence indicates that macrophage populations in various tissues and developmental stages derive from three distinct ontogenetic waves: primitive yolk sac–derived macrophages, fetal liver–derived monocytes, and bone marrow–derived monocytes.

Embryonic macrophages encompass both early yolk sac–derived macrophages and fetal liver–derived monocytes (7). In mouse models, the first wave originates from yolk sac erythro-myeloid progenitors (EMPs) at embryonic day 7.0 (E7.0). A subsequent wave of EMPs emerges around E8.5, migrates to the fetal liver, and differentiates into EMP-derived macrophages (8). These cells, often termed “pre-macrophages,” undergo rapid phenotypic diversification upon colonizing target tissues. Although EMP-derived macrophages initially populate embryonic tissues, they are progressively replaced by fetal liver–derived monocytes. By E10.5, hematopoietic stem cells (HSCs) from the aorta–gonad–mesonephros (AGM) region seed the fetal liver and later colonize the bone marrow by E17.5. Postnatally, monocyte-derived macrophages (MDMs) are maintained in each organ through continual replenishment by circulating HSC-derived monocytes (9, 10).

Kidney macrophages consist of both embryo-derived and monocyte-derived populations, with embryo-derived macrophages constituting the predominant subset. The proportions of embryo-derived macrophages within the total kidney macrophage population were 7.27 ± 0.4%, 46.7 ± 2.5%, and 98.8 ± 0.3% following induction at E8.5, E13.5, and E18.5, respectively (11). After birth, embryo-derived macrophages are maintained primarily through self-renewal mediated by the CX3C chemokine receptor 1 (CX3CR1)/CX3CL1 axis (12). Embryo-derived macrophages, which constitute the majority of kidney macrophages and serve as kidney resident macrophages (KRMs), together with MDMs, form the kidney macrophage compartment and cooperatively sustain kidney homeostasis. Under physiological conditions, the proportion of kidney macrophages derived from monocyte-derived macrophages (MDMs) progressively increases with age, reaching approximately 40% (11). In an adoptive transfer mouse model and irradiation, MDMs have the capacity to differentiate into KRMs, thereby preserving the integrity of the kidney niche (11, 13).

Earlier investigations have extensively examined macrophage heterogeneity and function through the conceptual framework of polarization—a paradigm that has become classical and remains widely adopted.

Macrophage differentiation has been broadly categorized into classical M1-type and alternative M2-type activation, mirroring the T helper 1 (TH1) and T helper 2 (TH2) paradigms of T cell differentiation (3, 14).

M1 polarization is driven by pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and pro-inflammatory cytokines—particularly Th1-derived cytokines such as tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) (15). Hallmarks of M1 polarization include the upregulation of surface activation markers and antigen presentation molecules, including major histocompatibility complex (MHC) class II, CD16, CD32, CD80, CD86, secreted phosphoprotein 1 (SPP1), and the interleukin (IL)-1 receptor (IL-1R). M1 macrophages also produce a diverse repertoire of pro-inflammatory mediators, such as IL-1, IL-6, IL-12, IL-23, inducible nitric oxide synthase (iNOS), matrix metalloproteinase-12 (MMP-12), and macrophage-inducible C-type lectin (MINCLE) (3, 16), all of which contribute to inflammatory processes.

In contrast, M2 macrophages exert diverse functions in immune regulation, notably in suppressing inflammation and promoting tissue repair. M2 polarization is driven by Th2-derived cytokines such as IL-4, IL-10, and transforming growth factor-β (TGF-β) (15). M2 macrophages are commonly identified by the expression of markers such as arginase 1 (Arg1), the mannose receptor (CD206), ferroportin 1 (FPN1, SLC40A1), and TGF-β (2, 17). They are further subclassified into four phenotypically and functionally distinct subtypes: M2a, M2b, M2c, and M2d (3, 18).

The classical M1/M2 polarization model remains widely employed in describing kidney macrophages. In the early stages of kidney injury, M1 macrophages predominate, functioning to clear apoptotic cells. Furthermore, M1 macrophages, together with T cells and dendritic cells (DCs), contribute to the formation of lymphoid aggregates, thereby establishing a pro-inflammatory microenvironment that amplifies kidney inflammatory responses (19). As the disease progresses into the reparative phase, M2 macrophages become the dominant subset, exerting anti-inflammatory and pro-repair effects (20). However, when tissue repair fails, M2 macrophages can also acquire pro-fibrotic properties.

Current perspectives posit that macrophages exist along a continuum of phenotypes encompassing M1-like, M2-like, and mixed states (21–23).

Macrophages should not be viewed merely as binary responders to polarizing cues. Instead, in response to specific microenvironmental stimuli, they possess the capacity to differentiate into diverse subpopulations equipped to perform highly specialized functions (24, 25).

Perivascular macrophages (PVMs) reside adjacent to blood vessels (26), where they regulate vascular permeability, maintain tissue homeostasis, and modulate endocrine function (26); they also act as a barrier against exogenous toxins but can promote pathological angiogenesis in tumors, facilitating metastasis (27–29). Iron-recycling macrophages, characterized by ferroportin 1 (FPN1) expression and rely on colony-stimulating factor 1 (CSF1) and the transcription factor (NRF2) (30), clear senescent or damaged erythrocytes to maintain systemic and cellular iron homeostasis (31). Sympathetic neuron–associated macrophages (SAMs), marked by solute carrier family 6 member 2 (SLC6A2) and Monoamine Oxidase A (MAOA) expression, metabolize norepinephrine in the sympathetic nervous system and influence thermogenesis, with presence confirmed in human sympathetic ganglia (32). Lipid-associated macrophages (LAMs), enriched in metabolic disorders such as atherosclerosis, nonalcoholic steatohepatitis (NASH), and obesity (33), are specialized in lipid handling and apoptotic cell clearance (34–37), but may also potentiate inflammation and aggravate disease progression (38, 39). Efferocytic macrophages specialize in apoptotic cell clearance via receptor-mediated or bridging molecule–mediated recognition, leveraging apoptotic cell–derived nucleotides to boost phagocytic activity, thereby reducing apoptotic burden and preventing secondary tissue injury (40, 41).

Several of the aforementioned functional types of macrophages are identified in the kidney. Researchers found a subset of embryonically derived KRMs (phenotypically similar to SAM) that localize in close proximity to kidney sympathetic nerves and are indispensable for maintaining sympathetic innervation, and highly express sympathetic nerve–relevant genes including MAOA, Neuropeptide Y receptor type 1 (Npy1r), and SLC6A2 (42). Patients with ANCA-associated glomerulonephritis (AGN) have a marked enrichment of SPP1⁺ LAMs within the kidney, where they contribute to both pro-inflammatory and pro-fibrotic processes (43). In addition, efferocytic capacity of macrophages is adversely associated with the progression of diabetic kidney disease (DKD), suggesting a protective role of efferocytic macrophages in DKD (23). Furthermore, manipulation of the labile iron pool in kidney macrophages mitigate CKD mice model, implying the involvement of iron recycling macrophage in CKD (44).

Together, examining macrophage heterogeneity through a functional lens provides a more refined understanding of their subpopulation-specific roles, advancing our mechanistic insight into their contributions in the kidney under both physiological and pathological conditions.

Initially, MDMs (Cd11b^high, F4/80^low) and KRMs (Cd11b^low, F4/80^high) were distinguished on the basis of differential expression of CD11b and F4/80 (45). Subsequent studies identified CD64 and C-C chemokine receptor type 2 (CCR2) as complementary markers for KRMs and MDMs, respectively (29, 46). Investigators further refine the subclassification of kidney macrophage subsets. For example, Some investigators have classified kidney macrophages into three distinct subsets based on the expression of CX3CR1 and CD81 (CX3CR1^-CD81^-, CX3CR1⁺CD81^-, and CX3CR1⁺CD81⁺) (47).

Mouse studies suggest that the development of the kidney is dependent on the regulatory functions of macrophages. At E9.5-E10.5, yolk sac–derived macrophages actively promote ureteric bud branching and tubulogenesis through the CSF-1/CSF1R signaling pathway (48), and contribute to early nephron patterning by clearing excess rostral nephron progenitors, thereby facilitating precise tissue organization (49). At E11.5-E12.5, macrophage–endothelial interactions are vital for vascular development, supporting vasculogenesis, vascular anastomosis, and the stabilization of kidney vascular architecture (49). At E12, fetal liver–derived macrophages start to infiltrate the mesenchyme of the developing metanephros, contributing to the formation of nephron components within both the cortical and medullary regions, including the loop of Henle (49, 50). The postnatal expansion and maturation of kidney macrophages parallel kidney growth, suggesting that they may play a role in this process (11).

Kidney macrophages are essential for maintaining the reabsorptive functions of the renal tubules. Sympathetic stimulation triggers the release of norepinephrine, which promotes sodium and water reabsorption while concurrently reducing kidney perfusion. Emerging evidence suggests that embryonic-derived macrophages are essential for maintaining the basal distribution and functionality of sympathetic fibers, thereby safeguarding against electrolyte imbalances and preventing disorders associated with excessive urinary excretion of Na⁺, K⁺, and Cl^- (42, 51). In addition, cortical macrophages in the kidney exhibit elevated expression of the phosphate transporter solute carrier family 34 member 1 (SLC34A1), enabling the active reabsorption of phosphate from the urinary filtrate and thereby mitigating the risk of urinary stone formation (52). The kidney tubular epithelium forms a tight barrier that segregates urinary solutes from the interstitium. Subepithelial macrophages, strategically positioned beneath the epithelial layer, can extend cellular protrusions across the epithelium to sample and monitor the contents of the urine. This dynamic surveillance mechanism facilitates the removal of particulate matter and contributes to tubular integrity and function (53).

Under physiological conditions, kidney macrophages act as immune sentinels, continuously conducting surveillance to maintain tissue homeostasis. Upon detection of PAMPs or DAMPs, macrophages rapidly recognize these cues via pattern recognition receptors, initiating downstream signaling cascades that shape the broader kidney immune landscape (2, 3). Perturbation of this surveillance system may precipitate a variety of pathological conditions. KRMs are capable of recognizing small immune complexes (SICs), thereby triggering excessive immune activation that culminates in a type III hypersensitivity reaction (29). In renal cell carcinoma (RCC), tumor-associated macrophages (TAMs) (predominantly M2-like) facilitate immune evasion by promoting immunosuppression and upregulating PD-L1 expression within the tumor microenvironment. In clear cell renal cell carcinoma (ccRCC), TAMs secrete IL-23, thereby exacerbating immune evasion (54). Kidney macrophages participate in host defense against exogenous pathogens, such as uropathogenic Escherichia coli (UPEC), by phagocytosis, yet their simultaneous suppression of adaptive immunity and potential to induce hyperinflammatory injury contribute to disease persistence and kidney tissue damage (55, 56).

During kidney injury, macrophages are either locally activated or arise from circulating monocytes recruited to the damaged tissue (57–60). The C-C motif chemokine ligand 2 (CCL2)/CCR2 signaling axis is traditionally recognized as a principal mechanism for monocyte recruitment, particularly in DKD, IgA nephropathy (IgAN), and ischemia–reperfusion injury (IRI) (61–64). The injured kidney establishes a pro-inflammatory microenvironment that activates macrophages (65). In glomerulonephritis, damaged endothelial cells promote the conversion of CCR2⁺ monocytes into proinflammatory macrophages through the TNF/tumor necrosis factor receptor 2 (TNFR2) signaling axis, thereby exacerbating the inflammatory response (62). Injured tubular epithelial cells release DAMPs, such as self-DNA, HMGB1, etc. to activate downstream innate immune response including the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway (66), the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in macrophages (67, 68). Together, these processes promote the conversion of macrophages into a proinflammatory phenotype. Additionally, phosphoinositide 3-kinase (PI3K) may facilitate macrophage infiltration into the kidney, thereby exacerbating kidney injury and fibrosis (58, 69, 70).

Activated macrophages contribute to kidney injury via multiple mechanisms (57). They secrete pro-inflammatory cytokines, such as IL-1β and TNF-α, that induce apoptosis and necrosis in glomerular and tubular epithelial cells, impairing filtration and reabsorption (67, 71). They also produce cytotoxic molecules such as the macrophage-inducible C-type lectin (Mincle), which recognizes necrotic tubular cells and amplifies inflammatory cytokine production while impeding clearance of dead cells in IRI (72). This establishes a self-perpetuating inflammatory cycle, in which junctional adhesion molecule-like protein (JAML) plays a critical role (73). Moreover, macrophages generate reactive oxygen species (ROS), directly damaging kidney macromolecules and exacerbating tissue injury (74).

As kidney repair progresses, macrophages undergo phenotypic transition toward a pro-repair phenotype (20, 75) (76). Although macrophages are involved, tubular epithelial cells remain the principal compartment contribute to the clearance of cellular debris and apoptotic bodies within the damaged microenvironment (77, 78). In addition to their scavenging functions, macrophages secrete a range of cytokines and growth factors—including IL-22 and Vascular Endothelial Growth Factor (VEGF)—that support angiogenesis and epithelial regeneration (79, 80).

Furthermore, kidney macrophages express anti-inflammatory mediators such as lipoxins, resolvins, and specialized pro-resolving lipid mediators (SPMs), which actively promote inflammation resolution and tissue homeostasis (81). For example, Maresin—a macrophage-derived SPM—facilitates lipid mediator class switching from pro-inflammatory to pro-resolving profiles, thereby supporting kidney repair (82).

Kidney macrophages can also participate in kidney fibrosis under pathological conditions (83–86). Under pro-fibrotic conditions, macrophages can adopt a fibrogenic phenotype, characterized by the secretion of TGF-β and VEGF, induction of epithelial-mesenchymal transition (EMT), and impaired mitophagy, which collectively promote the progression of fibrosis.

TGF-β not only promotes M2-like polarization via the Suppressor of Mothers Against Decapentaplegic (Smad) signaling axis but also induces macrophage-to-myofibroblast transition (MMT) (87). Excessive pro-fibrotic macrophage accumulation, fueled by persistent TGF-β/Smad activation, facilitates collagen and extracellular matrix (ECM) deposition, exacerbating fibrotic remodeling (88). In the UUO model, both Wnt family member 5A (Wnt5a)/Yes-associated protein (Yap)/Transcriptional co-activator with PDZ-binding motif (Taz) and β-catenin/Forkhead box protein O1 (Foxo1) signaling pathways have been shown to potentiate TGF-β-mediated fibrogenesis through macrophage-dependent mechanisms (89, 90).

Moreover, macrophages secrete exosomes that contain CD63 and tumor susceptibility gene 101 (TSG101) to promote the progression of fibrosis in DKD (91). Concomitantly, kidney macrophages promote kidney lymphangiogenesis by activating the VEGF-C/VEGFR3 axis, thereby contributing to fibrosis progression (92).

Macrophages also facilitate EMT in tubular epithelial cells, a key event in fibrogenesis whereby epithelial cells acquire mesenchymal traits (93). Additionally, macrophages support fibroblast survival by delivering platelet-derived growth factor (PDGF) ligands through direct cell–cell interactions (94–96). In the UUO model, macrophage recruitment is further sustained through MMP-9 derived from injured tubular endothelial cells, which also promotes EMT and accelerates fibrotic progression (97).

Disruption of phosphatase and tensin homolog-induced kinase1 (PINK1)/mitofusin-2 (MFN2)/Parkin signaling pathway impairs mitochondrial quality control, driving macrophage polarization toward a pro-fibrotic phenotype, thereby exacerbating kidney fibrosis (98). Moreover, similar findings have been observed in CKD patients with interstitial fibrosis and tubular atrophy (99), Dysregulation of the kidney macrophage-specific mitochondrial quality control mechanism exacerbates fibrosis, unequivocally underscoring its substantial potential in preventing the progression of kidney fibrosis.

Moreover, MMT has garnered considerable attention (100), as it plays a pivotal role in driving the progression of kidney fibrosis. Increasing evidence indicates that targeting MMT could be a therapeutic strategy to attenuate fibrosis (101, 102).

Kidney macrophages, owing to their high heterogeneity and the complexity of the kidney microenvironment, exhibit non-canonical functions ( Figure 2 ).

Pharmacologic inhibition of the CCL2/CCR2 axis is a viable strategy for modulating macrophage-driven inflammation. Emapticap Pegol (NOX-E36), a CCL2 inhibitor, has demonstrated efficacy in reducing proteinuria in patients with DKD (61). Similarly, clinical trials involving CCX140-B, a CCR2 antagonist, have reported decreased proteinuria in patients with DKD and focal segmental glomerulosclerosis (FSGS), suggesting a potential renoprotective effect (126, 127). These agents act by attenuating macrophage recruitment and activation, thereby disrupting inflammatory amplification loops.

Fostamatinib, an inhibitor of spleen tyrosine kinase (Syk), has shown therapeutic benefit in patients with IgA nephropathy and ANCA-associated vasculitis, partly by limiting macrophage infiltration. (128, 129).

Moreover, Extracellular vesicles based IL-10 delivery to kidney macrophages mitigates IRI-induced AKI, possibly through downregulation of the mTOR pathway (130).

Metformin, widely prescribed as a first-line agent for type 2 diabetes mellitus (T2DM) (131), has demonstrated potential renoprotective effects in large-scale cohort studies (132). Mechanistically, metformin activates AMP-activated protein kinase (AMPK), leading to the suppression of TGF-β expression (86, 133). This pathway mitigates macrophage polarization toward the M2 phenotype, thereby decelerating fibrotic remodeling in CKD. In a murine model of calcium oxalate (CaOx) crystal-induced kidney injury, metformin was shown to attenuate fibrosis and improve kidney function by modulating macrophage activation (134). However, high-dose metformin has been associated with deleterious effects in AKI, likely due to excessive neutrophil recruitment (135).

In addition, macrophages regulate ECM remodeling by modulating MMPs and tissue inhibitors of metalloproteinases (TIMPs), which inhibit MMP activity, leading to ECM accumulation and fibrosis (136).

Cell-based therapies have emerged as a promising frontier in clinical implications, and macrophage-based strategies are gaining substantial traction within kidney research. Researchers have developed a CAR-M capable of recognizing TNF and activating the intracellular IL-4 signaling pathway, thereby conferring anti-inflammatory functions in IRI-induced AKI (137). Genetically engineered macrophages overexpressing carnitine palmitoyltransferase 1a (CPT1a) exhibit augmented phagocytic activity by facilitating fatty acid oxidation and extracellular matrix clearance, suppressing pro-fibrotic cytokine release in CKD (138, 139). In addition, adoptive transfer of macrophages engineered to overexpress Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) enhance the anti-inflammatory phenotype of kidney macrophages by PI3K/protein kinase B (AKT) pathway, resulting in reduced fibrosis and improved kidney function in CKD (140).

In summary, a substantial body of research has already focused on targeting kidney macrophages, aiming to modulate their polarization, phenotype, and function to achieve anti-inflammatory and anti-fibrotic effects, as well as to develop macrophage-based cell therapies, thereby attenuating disease progression.