Open Access

Immune podocytes in the immune microenvironment of lupus nephritis (Review)

  • Authors:
    • Ruiling Liu
    • Xiaoting Wen
    • Xinyue Peng
    • Miaomiao Zhao
    • Liangyu Mi
    • Jiamin Lei
    • Ke Xu
  • View Affiliations

  • Published online on: September 14, 2023     https://doi.org/10.3892/mmr.2023.13091
  • Article Number: 204
  • Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder caused by the loss of tolerance to endogenous nuclear antigens such as double‑stranded DNA, leading to the proliferation of T cells and subsequent activation of B cells, which results in serious organ damage and life‑threatening complications such as lupus nephritis. Lupus nephritis (LN) develops as a frequent complication of SLE, accounting for >60% of SLE cases, and is characterized by proteinuria and heterogeneous histopathological findings. Glomerular injury serves a role in proteinuria as podocyte damage is the leading contributor. Numerous studies have reported that podocytes are involved in the immune response that promotes LN progression. In LN, immune complex deposition stimulates dendritic cells to secrete inflammatory cytokines that activate T cells and B cells. B cells secrete autoantibodies that attack and damage the renal podocytes, leading to renal podocyte injury. The injured podocytes trigger inflammatory cells through the expression of toll‑like receptors and trigger T cells through major histocompatibility complexes and CD86, thereby participating in the local immune response and the exacerbation of podocyte injury. Based on the existing literature, the present review summarizes the research progress of podocytes in LN under the local immune microenvironment of the kidney, explores the mechanism of podocyte injury under the immune microenvironment, and evaluates podocytes as a potential therapeutic target for LN.

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a mild rash, joint pain and multi-organ damage. The global SLE incidence and prevalence are estimated to be 5.14 (1.4 to 15.13) per 100,000 person-years and 43.7 (15.87 to 108.92) per 100,000 individuals (1). The hallmark of SLE is the defective clearance of dead cells by the immune system and the loss of tolerance to endogenous antigens such as double-stranded (ds)DNA, resulting in the abnormal activation of the immune system. This activation leads to immune-mediated attacks on organs and tissues, including lung, gut and kidney involvement (2). In particular, the kidneys are affected, leading to the development of lupus nephritis (LN) as the most severe manifestation of SLE and the common cause of morbidity and mortality in patients with SLE. In patients with SLE, >60% suffer from LN, and 40% of them progress to end-stage renal disease (ESRD) (3,4), which endangers the lives and health of the individuals, with the exact incidence contingent upon ethnicity and sex (5). The immune system contributes to the development of SLE. The two main cell types in the adaptive immune system, B cells and T cells, are both indispensable for the development of LN. B cells are pathogenic in SLE through the autoantibodies (such as anti-dsDNA antibodies and anti-nucleosome antibodies) and cytokines they produce. T cells drive both the systemic and intra-renal activation of B cells (6). In addition, genes for SLE also cause LN. Renal aggression during SLE is triggered by genes that undermine immune tolerance and stimulate autoantibody production. These genes may collaborate with other genetic factors to amplify innate immune signaling and type α interferon (IFN-α) production, consequently leading to the recruitment of leucocytes, inflammatory mediators and autoantibodies into end organs, notably the kidneys (7). Currently, high-doses of hormones (glucocorticosteroid) combined with immunosuppressants (methotrexate) are first line therapeutics for LN treatment. Short-term complete renal response rates are only 10–40% at 12 months, long-term outcomes have not improved further, and as many as 30% of LN patients will still progress to ESRD (8,9).

Podocyte injury is involved in the occurrence and development of LN, a disease that is associated with the progressive loss of renal function and various renal pathological features, including mesangial cell proliferation and subendothelial immune complexes. Podocytes are terminal epithelial cells that protrude into the glomerular urinary space and constitute an important component of the glomerular filtration barrier. Immune complex deposition in the renal tissues activates the complement system and thereby contributes to the failure in the efficient clearance of cellular fragments, triggering both the innate and adaptive immune systems. The production of cytokines such as IFN-α stimulates the antigen presentation and overactivation of T and B cells (7). Ultimately, additional inflammatory cytokines and chemokines promote the recruitment of inflammatory cells to the kidney and cause podocyte injury in the glomerulus (10). Numerous studies have reported the involvement of podocyte injury in LN (1113) and have suggested that podocytes can serve as biomarkers of LN activity (14). A new concept called ‘lupus podocytopathy’ has been proposed (15), which refers to patients with LN with normal glomeruli but a diffuse disappearance of foot processes and podocyte damage. However, podocyte injury in patients with LN with normal glomeruli is often overlooked in clinical practice, which delays timely treatment and accelerates the deterioration of renal function. Therefore, investigating the role of podocyte injury in LN is warranted.

The immune microenvironment is considered as the environment of the local immune response. It is composed of diverse populations including infiltrating immune cells, immune molecules and humoral components. Immune complex deposition, local complement activation, along with immune cell recruitment and local intrarenal cytokine signaling account for glomerular injury in the LN immune microenvironment (10). Renal immune cells accumulate in the kidneys of the patients with LN, which involves the formation of tertiary lymphoid structures (TLS) (16). The TLS consists of immune cells, cytokines and resident renal cells in LN, and the activation of immune cells triggers a transient aggravation of resident cell injury and even the production of autoantibodies within the kidneys, exacerbating disease progression (17).

LN develops from a loss of immune balance to ubiquitous autoantigens, which is a result of inflammation and immune responses. Although the immunomolecules and immune cells in the renal immune microenvironment have important roles, the underlying mechanisms of the immune responses in the podocyte injury of LN remain unclear. The present review aimed to summarize the current understanding of the immune microenvironment of podocytes in LN, provide an update on their interaction mechanisms and offer the rationale for the podocytes as novel therapeutic targets in the treatment of LN.

Pathogenesis of LN

LN is the most common complication of SLE, and proteinuria and hematuria are the primary clinical manifestations. The salient features of LN are associated with the deposition of immune complexes, which cause an inflammatory and immune response in the kidney (18). In vivo apoptosis or secondary necrosis (19) is responsible for the chromatin fragment exposure. The exposed DNA or nucleosomes bind with corresponding autoantibodies to form immune complexes and deposit onto the glomerular basement membrane. Concurrently, after associating with immune complexes in the glomeruli, nucleosomes within necrotic intrinsic glomeruli cells form in situ immune complexes containing both DNA and nucleosomes (20).

The nucleic acid components of the immune complexes collectively stimulate intrarenal inflammation by binding to toll-like receptors (TLRs) and Fc receptors (FcRs) or by activating immune responses through the complement cascade. Additionally, the ligation of TLRs induces the maturation of plasmacytoid dendritic cells (pDCs) and facilitates the secretion of proinflammatory cytokines and chemokines including interferon (IFN)-α (21,22). Secreted IFN-α promotes the activation of antigen-presenting dendritic cells (DCs), thereby promoting the differentiation of self-reactive B cells to plasma cells and enhancing the production of memory T cells, which form germinal center structures (23).

B-cell activating factor (BAFF) emerges as an inducer of B cell proliferation, differentiation and maturation through the CD40 ligand (CD40L) and CD28, on the surface of T cells migrating into the glomeruli, binding with CD40 and B7 on B cells, respectively (17). Subsequently, the autoantibodies produced bind to autoantigens and deposit in situ in the kidney. In addition to secreting antibodies, activated B cells, as a type of antigen-presenting cell (24), promotes the activation of pathogenic T cells to secrete proinflammatory cytokines such as IL-6 and TNF-α, and facilitate the recruitment of macrophages and DCs into the glomerulus and the tubulointerstitium (25). Immune cells also undergo intrarenal proliferation and activation by binding to the FcRs of immune complexes. Activated neutrophils and macrophages secrete reactive oxygen species and proteases, which directly damage the kidneys (26). In addition, immune complexes also activate the complement pathway to form membrane attack complexes, releasing anaphylatoxins to promote inflammatory reactions and accelerate the progression of LN (27) (Fig. 1).

Basic structure and function of podocytes

The podocyte, a terminally and highly differentiated epithelial cell located in the urinary space, consists of a foot process and an apical surface domain. Given that podocytes act as essential components of the glomerular filtration barrier, the apical surface domain carries a negative charge and restricts the passage of negatively charged proteins (28). Foot processes attach to the glomerular basement membrane through integrins, syndecans, dystroglycan and other adhesion molecules (28). During podocyte development, a number of large extensions are formed by the epithelial cells, therefore, primary foot processes split into secondary and tertiary processes, which are abundant in microtubule structures (29). The foot processes are primarily composed of actin, which constitutes the cellular cytoskeleton of the podocyte. The function of actin is to connect the apical and basal membrane domains, as well as the slit diaphragm. The parallel contractile actin bundles are controlled to regulate the permeability of the filtration barrier (30). Destruction of podocyte actin leads to podocyte injury, disappearance of foot process fusion, damage to the filtration barrier and to proteinuria. Adjacent foot processes interdigitate with each other, forming slit diaphragms that anchor to the glomerular basement membrane. Nephrin, podocin, CD2-associated protein (CD2AP) and other molecules compose the slit diaphragm, participating in intracellular signaling and the formation and maintenance of the filtration barrier (Fig. 2).

Nephrin, a member of the immunoglobulin superfamily, interacts with the actin cytoskeleton through Nck adapter proteins and maintains the integrity of the podocyte structure and the filtration barrier (29). Nephrin affects the assembly of actin polymers in cell membranes. Decreased levels of nephrin leads to abnormal tertiary podocytes, loss of normal polarity and abnormal intercellular junctions, as a result of proteinuria. Neph1 is another transmembrane protein located near to nephrin in the cell membrane (31). Neph1, a major regulator of actin dynamics, is indispensable in maintaining normal slit diaphragm function. The phosphorylated nephrin-Neph1 complexes can lead to the reassembly of actin complexes, exerting irreversible effects on podocyte filtration function (32). Podocin is a membrane-associated protein that is crucial for signal transduction of the nephrin-Neph1 complex. The reduction in nephrin level caused by podocin mutations will alter the signaling of the nephrin-Nephl complex and result in an impaired podocyte slit diaphragm (33). Podocin also regulates cellular cytoskeletal dynamics through the activity of transient receptor potential cation channel subfamily C member 6 (TRPC6). TRPC6 is a non-selective, calcium-permeable cation channel in the plasma membrane of podocytes, which stabilizes the actin cytoskeleton of podocytes to sense changes in pressure, fluid flow or filtration rate (34). CD2AP is a cytoplasmic protein that interacts with nephrin and podocin and also takes part in the actin filament assembly in the slit diaphragm of podocytes through cellular signal transduction (35). The downregulation of these slit diaphragm proteins can lead to the structural and functional damage of podocytes and the production of proteinuria.

Podocytes in the immune system

The occurrence and progression of LN involves multiple pathways, including abnormal cell death, autoantibody production, immune complex deposition, complement activation and the increased activation of immune cells (for example, T and B cells). Immune complex deposition predominates in the development of LN, and the majority of LN classifications by the International Society of Nephrology and the Renal Pathology Society involve immune complex deposition (Table I). Additionally, foot process fusion and podocyte injury have been observed in different classifications of LN (36). The deposition of immune complexes in the kidneys takes place by various mechanisms and activates complement components, inducing damage to podocytes through both the innate and adaptive immune responses. Furthermore, podocytes express immunomolecules and participate in immune responses (37) (Fig. 3).

Table I.

Classification of lupus nephritis and the condition of the podocytes after damage.

Table I.

Classification of lupus nephritis and the condition of the podocytes after damage.

TypeDisease namePathological manifestationsPodocyte condition after damage
Class IMinimal mesangial lupus nephritisMesangial immune complexesUnknown
Class IIMesangial proliferative lupus nephritisMesangial immune complexes and a small number of subepithelial or subendothelial complexesExtensive podocyte foot process effacement
Class IIIFocal lupus nephritisSubendothelial immune complexesExtensive podocyte foot process effacement
Class IVDiffuse lupus nephritisSubendothelial immune complexesPodocyte foot process effacement
Class VMembranous lupus nephritisSubepithelial immune complexesMarked disappearance of podocytes
Class VIAdvanced sclerotic lupus nephritisGlomerulosclerosis in ≥90% of the glomeruliDisappearance of podocytes
Podocytes in the innate immunity
Podocytes interact with the complement system

Multiple immune pathways engage in the pathogenesis of LN. The complement system serves a positive role in maintaining tolerance against LN for the efficient clearance of cellular fragments. Increasing evidence suggests that complement can mediate podocyte injury (3840). In membranous nephropathy, complement mediates podocyte injury by inducing cell scorch death through mitochondrial dysfunction (40). When the formation of immune complexes exceeds clearance pathways, complement components C1q, C5a and C5b-9 are released and deposited in the kidney. Subiytic C5b-9 stimulates the podocytes to release cytokines, proteases and oxidants. It can also induce DNA damage, leading to restricted podocyte proliferation (41). In LN, activated intrinsic renal cells can also promote the release of proinflammatory mediators (IL-1β), and express multiple complement components.

Complement receptor 1 (CR1), which is exclusively expressed on podocytes, is reduced in severe glomerular lesions (42,43). Reduced expression levels of CR1 are considered to result from decreased synthesis due to podocyte injury rather than excessive depletion. The decrease in CR1 synthesis increases the sensitivity of podocytes to complement attack, further exacerbating podocyte injury (44). In Murphy Roths Large/lymphoproliferative (MRL/lpr) lupus mice, complement factor H (CFH) deficiency leads to immune complex deposition in the subendothelial and subepithelial regions of the kidney, disappearance of podocyte foot processes, and accelerated progression of LN (45). Podocytes were revealed as the targets and sources of kidney injury due to their production of complement components. Therefore, complement pathway inhibition has been considered as a potential treatment strategy for LN in clinical trials (46,47).

Podocytes interact with the TLRs

TLRs are expressed in innate immune cells (such as monocytes, macrophages and dendritic cells), which recognize pathogen-associated molecular patterns (PAMPs) and can also be activated by endogenous ligands. Studies have revealed that TLRs are expressed in mouse glomeruli and perform different physiological functions (48,49). TLR4 upregulated in podocytes in mice with membranoproliferative glomerulonephritis (MPGN) can destroy the kidney by directly releasing the chemokines, which may promote the recruitment of inflammatory cells and exacerbate glomerular injury (37).

TLR8 and TLR9 are overexpressed in BXSB/Yaa (a genetic mutation located on the Y chromosome, namely, Y-linked autoimmune acceleration) SLE mice models (49). TLR8 is mainly located in podocytes and its expression level is negatively correlated with nephrin expression and positively correlated with proteinuria levels in glomerulonephritis, suggesting that excessive levels of TLR8 are associated with podocyte injury progression (50). Therefore, it is important to monitor the changes of the TLR8 mRNA levels in the urine of patients, which reflects the podocyte injury status. In human LN pDCs recognize single-stranded RNA, 5′-C-phosphate-G-3′ DNA from bacteria and viruses as well as altered eukaryotic nucleic acids via TLR9 (51), which induces the release of type I IFNs and promotes local and systemic immune responses via increased expression levels of costimulatory molecules (52). TLR9 coexists with injury podocyte proteins, and its expression is associated with podocyte injury and the development of MPGN. TLR9 is only expressed in damaged podocytes during active LN while it is not detected in healthy human kidneys. This expression may be associated with increased levels of dsDNA antibodies and may be involved in the process of podocyte injury in LN (53,54).

In summary, TLRs can combine podocytes with the innate immunity, induce podocyte injury and mediate LN. Future research could focus on the role of TLRs in LN podocyte injury in order to inhibit the TLR-induced podocyte injury and prevent the progression of LN.

Podocytes interact with the innate immune cells

Macrophages are antigen-presenting cells that have the capacity to process and present antigens to T cells. Cytokines, such as TNF-α and IL-1β, produced by activated macrophages can directly inhibit the expression of the podocyte-specific protein nephrin, leading to podocyte injury and the induction of glomerulonephritis and proteinuria (55). The polarization of macrophages from a proinflammatory phenotype to an anti-inflammatory phenotype can prevent podocyte injury (55,56). Sung and Fu (57) revealed that infiltrating macrophages in the glomerulus can activate T cells and interact with podocytes through cytokines. Subsequently, the injured podocytes and mesangial cells produce the inflammatory cytokines IL-1β and IL-6, leading to an upregulation of adhesion molecules and chemokines from podocytes and thereby promoting the recruitment of macrophages to the glomerulus (58). After migrating to the glomerulus, macrophages are stimulated by immune complexes, complement and cytokines in the local glomerular environment to produce TNF-α and induce podocyte injury. This process represents a cascade amplification reaction that ultimately leads to severe glomerular damage in LN. Thus, inhibiting the process of macrophage-induced podocyte injury is necessary to prevent the progression of LN.

Podocytes interact with innate immune molecules

Nucleotide oligomerization domain (NOD)-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome is a multimeric protein that is associated with the secretion of inflammatory factors such as IL-1β (59). Previous studies have revealed that patients and mice with LN demonstrate NLRP3 activation in podocytes, which induces the secretion of IL-1β and inhibits the expression of the podocyte-specific protein nephrin, thereby disrupting the integrity of the podocyte filtration barrier, leading to proteinuria (60,61). Thus, inhibiting NLRP3 has been demonstrated to prevent the loss of foot processes in podocytes and prevent renal tissue damage, thereby reducing proteinuria (61).

DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) is an innate immune molecule with immune recognition functions that can be expressed on podocytes in LN. When podocytes are exposed in vitro to serum from mice with LN, the expression levels of DC-SIGN are upregulated, which promotes T cell proliferation and increases secretion of IFN-γ from CD4+ T cells. Therefore, it seems that DC-SIGN-expressing podocytes may share similar functions with DCs, stimulating T cell proliferation and exerting corresponding effects (62). In summary, the interaction between podocyte injury and the local innate immune responses in the kidney are both involved in the progression of LN.

Podocytes in the adaptive immunity
Podocytes interact with autoantibodies

In LN, IgG-based autoantibodies bind to antigens to form immune complexes that deposit in the kidneys, subsequently causing glomerular injury and proteinuria. Simultaneously, rearrangement of cytoskeletal components in podocytes induced by IgG reduces the expression levels of podocyte proteins (nephrin and synaptopodin) with structural podocyte damage in patients with LN. As the Fc receptor (FcR) is overexpressed in LN podocytes, IgG bound with FcR is endocytosed by the podocytes (63). Furthermore, endocytosed IgG upregulates Ca2+/calmodulin-dependent kinase IV in podocytes, which inhibits the expression of nephrin and results in podocyte injury. Additionally, the expression levels of CD86 on podocytes is increased by endocytosed IgG (64,65). CD86 is one of the co-stimulatory molecules in T cell activation, implying the potential engagement of podocytes in the initiation of renal T cell activation.

Bruschi et al (66) reported that patients with LN have antibodies that directly target podocytes, which are associated with high proteinuria in these patients. dsDNA antibodies are present at increased concentrations in renal tissue compared with that of the systemic circulation. It forms immune complexes and deposits them in the glomerulus, exhibiting podocyte injury and local immune reactions. These antibodies can also cross-react with -actinin-4 on podocytes, causing cytoskeletal rearrangement and complement activation, which directly leads to podocyte injury (67,68). Therefore, in addition to immune complex formation, the direct binding of podocyte-targeting autoantibodies present in the serum of patients can aggravate LN-associated proteinuria, leading to podocyte injury.

Overall, podocytes may provide antigenic targets for autoantibodies. Furthermore, podocyte injury is generated when autoantibodies form immune complexes that deposit in situ within the kidney in LN. In future studies, it will be important to identify other relevant antibodies that directly target intrinsic renal cells, such as podocytes, mesangial cells and the basement membrane, to further elucidate new mechanisms of kidney injury in LN.

Podocytes interact with adaptive immune cells

In addition to reacting with autoantibodies in the immune microenvironment, podocytes can also interact with immune cells. In crescentic glomerulonephritis, rupture of Bowman's capsule can release CD8+ T cells into the glomerulus, leading to podocyte injury (69). Compared with healthy mice and people, the podocytes of lupus mice and patients with LN have high expression levels of CD80 and CD86, which may promote T cell expansion and aggregation within the renal parenchyma. Increases in CD80 levels are positively associated with the severity of proteinuria (70). In vitro experiments have revealed that CD80 activation leads to the reorganization of slit diaphragm proteins, nephrin and podocin, and the disruption of actin filaments, and also leads to integrin inactivation to promote podocyte migration and damage (71,72). CD80 and CD86 expressed in podocytes are a potentially rich source of biomarkers that may capture various aspects of the renal injury.

Coers et al (73) and Goldwich et al (74) demonstrated that podocytes can express major histocompatibility complex (MHC) I and II, as well as macrophage markers (CD68, F4/80, and CD206) and co-stimulatory molecules (CD80). In the inflammatory environment, podocytes came into close contact with glomerular infiltrating T cells (74), which can activate CD4+ T cells and CD8+ T cells (74). Podocytes can cross-present endocytosed IgG to local infiltrating T cells via MHC, activating T cells to induce podocyte injury and apoptosis (75). Therefore, these findings suggest that podocytes in LN participate in the local immune response, which is identical to the role of antigen-presenting cells, contributing to the pathogenesis of LN.

Local infiltration of CD4+ T cells in the kidney promotes the progression of nephritis (76). Lipopolysaccharide (LPS)-induced podocytes polarize naive CD4+ T cells into T helper-17 (Th17) and regulatory T (Treg) cells, affecting the Th17/Treg balance and producing large amounts of proinflammatory cytokines. Th17 cells can secrete IL-17A, which has the potential to promote podocyte cytoskeletal rearrangement (77), and is probably the reason for the positive correlation between IL-17A levels and proteinuria in patients with LN (78,79). Following the stimulation of IL-17A secretion by Th17 cells, podocytes can express IL-17A receptors and produce the NLRP3 inflammasome, resulting in increased secretion of IL-1β. Additionally, IL-17A can disrupt podocyte morphology and induce podocyte injury (80). Preventing CD4+ T cell activation in the renal immune microenvironment and maintaining Th17/Treg balance may provide a new potential therapeutic strategy for LN. However, further research is required for in vivo validation and investigation of the mechanisms of action (81).

In LN, intrarenal B cells can form germinal center-like structures and locally produce pathogenic antibodies (82,83). Kolovou et al (84) described that oligoclonal B cells are associated with podocyte injury and glomerulosclerosis in LN, but oligoclonal expansion of B cells failed to be detected in the peripheral blood of patients with LN. This is possibly due to the inflammatory stimulus promoting B cell proliferation in the local renal environment. The interaction between B cells and podocytes in the immune microenvironment leads to podocyte injury, but the specific mechanism is unclear and further research is needed to elucidate the role of intrarenal B cells in podocyte injury. Cardiotrophin-like cytokine factor 1 (CLCF-1), also known as B cell-stimulating factor, can regulate B cell differentiation and Ig class switching when overexpressed (85). Moreover, CLCF-1 is currently considered as a potential therapeutic target as it can affect kidney development (86), and activate the Janus kinase (JAK)/STAT pathway and change podocyte morphology in focal segmental glomerulosclerosis, leading to renal dysfunction and proteinuria (87).

Therefore, the progression of LN may be caused by the interaction between substances in the immune microenvironment and podocytes and it is necessary to explore this interaction.

Immune microenvironment of podocytes in animal models

Previously, four lupus mouse models have been established, including spontaneous lupus mouse models, induced lupus mouse models, genetically modified lupus mouse models and humanized lupus mouse models. Currently, the spontaneous lupus mouse model is commonly used to study the interaction between podocytes and the immune microenvironment. The spontaneous lupus mouse models include New Zealand Black (NZB), NZB × New Zealand White (NZB/W) first filial generation (F1), MRL/lpr and BXSB/Mp (BXSB/Yaa). These models produce SLE-like autoimmunity, with the production of autoantibodies including anti-nuclear, anti-dsDNA and anti-histone. Clinical manifestations of SLE have also been observed, such as immune complex-mediated glomerulonephritis and polyclonal hypergammaglobulinemia and foot process effacement (88) (Table II).

Table II.

Summary of LN mouse models.

Table II.

Summary of LN mouse models.

Mouse modelAutoantibodiesMain clinical featuresAge of mice at mortalityMain research area(Refs.)
NZBAnti-dsDNA, anti-RBC and anti-gp70LN, IC-type GN, autoimmune hemolytic anemia and hypocomplementemia15 and 18 months because of autoimmune hemolytic anemiaInflammatory factors and immune complex deposition(60,61,102,103)
NZB/WF1ANA, anti-dsDNA, anti-Ro, anti-La, anti-Sm, anti-RBC and anti-RNALN, lymphadenopathy, splenomegaly, mild vasculitis, lymphadenopathy and hemolytic anemia10 and 12 months because of renal failureInflammatory factors, podocyte injury and immune complex deposition(89)
MRL/lprANA, anti-dsDNA, anti-ssDNA, anti-Sm, anti-Ro, anti-La, rheumatoid factor, anti-RBC and snRNPLN, hypergammaglobulinemia, high titers of autoantibodies, circulating ICs, lymphadenopathy, polyarthritis, vasculitis and splenomegaly5 and 12 months due to renal failureImmune complex deposition, complement system, podocyte injury and specific pathogenic mechanisms involved in kidney disease(45,90,91)
BXSB/YaaANA, anti-dsDNA and anti-RBCLN, IC-mediated GN, secondary lymphoid node hyperplasia, hypergammaglobulinemia and monocytosis5-8 months for BXSB/Yaa male mice and ~15 months for BXSB female mice complex because ofExpression levels of the TLR, podocyte injury and immune deposition renal failure(46,50,54,93)

[i] NZB, New Zealand Black; NZB/W, NZB × New Zealand White; F1, first filial generation; MRL/lpr, Murphy Roths Large/lymphoproliferative, a mouse strain with the lymphoproliferation (lpr) mutation; BXSB/Yaa,a mouse strain with the Y-linked autoimmune accelerator mutation; RBC, red blood cell; gp70, 70 kDa glycoprotein; ANA, anti-nuclear antibodies; dsDNA, double-stranded DNA; Sm, Smith; Ro, a nuclear protein; La, a nuclear protein; ssDNA, single-stranded DNA; snRNP, small nuclear ribonucleoproteins; IC, immune complex; GN, glomerulonephritis; TLR, toll-like receptor; LN, lupus nephritis.

NZB/W F1 mice are a model for studying renal lesions in SLE. These mice have a susceptibility to autoimmunity and exhibit podocyte damage, reduced nephrin and podocin expression levels and proteinuria production. Immune complex deposition and crescent formation can be observed in the glomeruli, with mild mesangial hyperplasia in the early stages of murine development and focal and diffuse proliferative histological forms in the late stages of murine development, culminating in renal failure (89).

MRL/lpr mice are a model of spontaneous recessive mutant lymphocyte proliferation that can present with immune complex deposition-mediated glomerulonephritis, with a proliferative LN histological pattern characterized by endothelial and mesangial cell proliferation and thickening of the basement membrane (90). MRL/lpr mice are commonly used to investigate the mechanisms of podocyte injury and specific pathogenic mechanisms in diseases affecting the kidneys. CFH deficiency in this mouse model leads to immune complex deposition, loss of podocyte foot processes, accelerated renal injury and LN progression (45). When MRL/lpr mice are stimulated with LPS, levels of proinflammatory cytokines increase in the serum, and there is damage to the podocytes in the kidney, as well as increased urinary albumin (91).

BXSB/Yaa mice are a male lupus-like autoimmune disease model (92) that develops severe immune complex-mediated glomerulonephritis with podocyte injury and foot process effacement. This model also develops membranoproliferative LN with IgG and C3 deposition in the mesangium (46). The overexpression of the TLR was correlated with urinary albumin levels and mRNA levels of the nephrin in the BXSB-Yaa mice, which are commonly used to investigate the interaction between TLRs and podocytes. The BXSB/Yaa mouse model is the result of a gene mutation that causes translocation of the terminal region of the X chromosome to the Y chromosome, leading to TLR7 gene duplication, which increases TLR7 expression levels (93). Additionally, BXSB/Yaa mice demonstrate overexpression of the TLR8 in the glomerulus, which is negatively correlated with podocyte markers (nephrin, podocin and synaptopodin), inducing autoimmune responses. The mRNA expression level of TLR8 is positively correlated with urinary albumin, suggesting the involvement of TLR8 in the process of podocyte injury (50).

New animal models are expected to be established to explore the specific pathogenic mechanisms of renal intrinsic cell autoantibodies in kidney disease. This will shed light on novel pathways leading to renal damage in LN.

Application of drug-targeted podocytes

In the last decade, prominent advances have been made in studying the structure and function of podocytes. Anifrolumab is a human monoclonal antibody targeting the type I IFN receptor subunit 1 and is the first type I IFN receptor antagonist approved by the US Food and Drug Administration for the treatment of SLE in adult patients. Meanwhile, anifrolumab has been investigated as a promising strategy for the treatment of LN in clinical trials (9496). A large randomized placebo-controlled trial suggested that neutralizing type I IFN receptors expressed by podocytes can effectively reduce proteinuria in patients with LN (97). Tacrolimus, a calcineurin inhibitor, can reduce proteinuria and improve kidney function in mice with lupus and patients with LN (98), while stabilizing the podocyte cytoskeleton and suppressing podocyte apoptosis, partially protecting podocytes from injury in LN (99). Baricitinib, a selective inhibitor of JAK1 and JAK2, is commonly used for rheumatoid arthritis treatment. Recent a study has revealed that baricitinib demonstrates benefits in inhibiting systemic autoimmunity in MRL/lpr mice and improves the lupus-like phenotype. It has been identified that baricitinib can inhibit the JAK/STAT pathway in podocytes, restore the abnormal podocyte structure caused by inflammation, and thus prevent renal damage (100). Greka et al (71) revealed that abatacept, a co-stimulatory blocker of B7-1, suppresses T cell activation and promotes integrin activation in podocytes. It also inhibits podocyte migration and prevents podocyte damage, which improves proteinuria in patients with LN.

Podocyte damage is reversible in LN, and actin is able to restore foot processes and reorganize the podocyte cytoskeleton. These studies illustrate a therapeutic target of podocytes in the glomerulus and immune cells in the immune microenvironment for precise treatment of LN, as they reduce systemic side effects of drugs, relieve proteinuria symptoms and improve disease progression.

Conclusion and future perspectives

Podocytes are glomerular epithelial cells, and the majority of all kidney diseases lead to podocyte injury. There is evidence that podocytes are important intrinsic cells of the kidney, which confer immune cell functions to promote the occurrence and development of LN. The manifestation and pathology of SLE in murine models, especially NZB/W F1 and MRL/lpr mice, are identical to that in patients with LN and have similar immune mechanisms. These help to further investigate the interaction mechanisms between podocytes and the renal immune microenvironment in LN. Recently, a number of studies have revealed that current therapies used to treat autoimmune diseases exhibit a direct protective effect on podocytes, alleviating the occurrence of proteinuria. These findings provide insights into targeted therapy for kidney diseases. Numerous studies have confirmed that LN podocytes participate in the innate and adaptive immune processes and interact directly with cells and molecules in the immune microenvironment. However, the mechanism of their interaction has not been thoroughly investigated. Therefore, further studies are needed to elucidate the interactions between LN podocytes and the local immune cells of the kidney, especially T and B cells. Targeting these pathogenic pathways might enable a more personalized approach to the treatment of LN and lead to improved outcomes for patients with LN.

Acknowledgements

Not applicable.

Funding

This work was supported by the National Natural Science Foundation of China and Shanxi Province Applied Basic Research Project (grant nos. 82202005 and 201901D211511), the National Natural Science Foundation of China (grant no. 81871292), the Key Research and Development (R&D) Projects of Shanxi Province (grant no. 201803D31136), the Four ‘Batches’ Innovation Project of Invigorating Medical Through Science and Technology of Shanxi Province (grant no. 2023XM002), and the Shanxi Province Postgraduate Practice Innovation Project (grant no. 2023SJ135).

Availability of data and materials

Not applicable.

Authors' contributions

RL and XP wrote the manuscript. MZ acquired and interpreted the data. LM and JL conceptualized and designed the manuscript. XW and KX reviewed and revised the manuscript. All authors read and approved the final version of the manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Tian J, Zhang D, Yao X, Huang Y and Lu Q: Global epidemiology of systemic lupus erythematosus: A comprehensive systematic analysis and modelling study. Ann Rheum Dis. 82:351–356. 2023. View Article : Google Scholar : PubMed/NCBI

2 

Kaul A, Gordon C, Crow MK, Touma Z, Urowitz MB, van Vollenhoven R, Ruiz-Irastorza G and Hughes G: Systemic lupus erythematosus. Nat Rev Dis Primers. 2:160392016. View Article : Google Scholar : PubMed/NCBI

3 

Tektonidou MG, Dasgupta A and Ward MM: Risk of end-stage renal disease in patients with lupus nephritis, 1971–2015: A systematic review and bayesian meta-analysis. Arthritis Rheumatol. 68:1432–1441. 2016. View Article : Google Scholar : PubMed/NCBI

4 

Seligman VA, Lum RF, Olson JL, Li H and Criswell LA: Demographic differences in the development of lupus nephritis: A retrospective analysis. Am J Med. 112:726–729. 2002. View Article : Google Scholar : PubMed/NCBI

5 

Aguirre A, Izadi Z, Trupin L, Barbour KE, Greenlund KJ, Katz P, Lanata C, Criswell L, Dall'Era M and Yazdany J: Race, ethnicity, and disparities in the risk of end-organ lupus manifestations following a systemic lupus erythematosus diagnosis in a multiethnic cohort. Arthritis Care Res (Hoboken). 75:34–43. 2023. View Article : Google Scholar : PubMed/NCBI

6 

Tsokos GC, Lo MS, Costa RP and Sullivan KE: New insights into the immunopathogenesis of systemic lupus erythematosus. Nat Rev Rheumatol. 12:716–730. 2016. View Article : Google Scholar : PubMed/NCBI

7 

Mohan C and Putterman C: Genetics and pathogenesis of systemic lupus erythematosus and lupus nephritis. Nat Rev Nephrol. 11:329–341. 2015. View Article : Google Scholar : PubMed/NCBI

8 

Costenbader KH, Desai A, Alarcón GS, Hiraki LT, Shaykevich T, Brookhart MA, Massarotti E, Lu B, Solomon DH and Winkelmayer WC: Trends in the incidence, demographics, and outcomes of end-stage renal disease due to lupus nephritis in the US from 1995 to 2006. Arthritis Rheum. 63:1681–1688. 2011. View Article : Google Scholar : PubMed/NCBI

9 

Parikh SV and Rovin BH: Current and emerging therapies for lupus nephritis. J Am Soc Nephrol. 27:2929–2939. 2016. View Article : Google Scholar : PubMed/NCBI

10 

Davidson A: What is damaging the kidney in lupus nephritis? Nat Rev Rheumatol. 12:143–153. 2016. View Article : Google Scholar : PubMed/NCBI

11 

Kraft SW, Schwartz MM, Korbet SM and Lewis EJ: Glomerular podocytopathy in patients with systemic lupus erythematosus. J Am Soc Nephrol. 16:175–179. 2005. View Article : Google Scholar : PubMed/NCBI

12 

Bomback AS and Markowitz GS: Lupus podocytopathy: A distinct entity. Clin J Am Soc Nephrol. 11:547–548. 2016. View Article : Google Scholar : PubMed/NCBI

13 

Wright RD and Beresford MW: Podocytes contribute, and respond, to the inflammatory environment in lupus nephritis. Am J Physiol Renal Physiol. 315:F1683–F1694. 2018. View Article : Google Scholar : PubMed/NCBI

14 

Moustafa FE, Soliman NA, Bakr AM and El Shwaf IM: Assessment of detached podocytes in the Bowman's space as a marker of disease activity in lupus nephritis. Lupus. 23:146–150. 2014. View Article : Google Scholar : PubMed/NCBI

15 

Hu W, Chen Y, Wang S, Chen H and Liu Z, Zeng C, Zhang H and Liu Z: Clinical-Morphological features and outcomes of lupus podocytopathy. Clin J Am Soc Nephrol. 11:585–592. 2016. View Article : Google Scholar : PubMed/NCBI

16 

Jamaly S, Rakaee M, Abdi R, Tsokos GC and Fenton KA: Interplay of immune and kidney resident cells in the formation of tertiary lymphoid structures in lupus nephritis. Autoimmun Rev. 20:1029802021. View Article : Google Scholar : PubMed/NCBI

17 

Kang S, Fedoriw Y, Brenneman EK, Truong YK, Kikly K and Vilen BJ: BAFF induces tertiary lymphoid structures and positions T cells within the glomeruli during lupus nephritis. J Immunol. 198:2602–2611. 2017. View Article : Google Scholar : PubMed/NCBI

18 

Schwartz N, Goilav B and Putterman C: The pathogenesis, diagnosis and treatment of lupus nephritis. Curr Opin Rheumatol. 26:502–509. 2014. View Article : Google Scholar : PubMed/NCBI

19 

Dieker J, Tel J, Pieterse E, Thielen A, Rother N, Bakker M, Fransen J, Dijkman HB, Berden JH, de Vries JM, et al: Circulating apoptotic microparticles in systemic lupus erythematosus patients drive the activation of dendritic cell subsets and prime neutrophils for NETosis. Arthritis Rheumatol. 68:462–472. 2016. View Article : Google Scholar : PubMed/NCBI

20 

Elkon KB: Review: Cell death, nucleic acids, and immunity: Inflammation beyond the grave. Arthritis Rheumatol. 70:805–816. 2018. View Article : Google Scholar : PubMed/NCBI

21 

Salvi V, Gianello V, Busatto S, Bergese P, Andreoli L, D'Oro U, Zingoni A, Tincani A, Sozzani S and Bosisio D: Exosome-delivered microRNAs promote IFN-α secretion by human plasmacytoid DCs via TLR7. JCI Insight. 3:e982042018. View Article : Google Scholar : PubMed/NCBI

22 

Leonard D, Eloranta ML, Hagberg N, Berggren O, Tandre K, Alm G and Rönnblom L: Activated T cells enhance interferon-α production by plasmacytoid dendritic cells stimulated with RNA-containing immune complexes. Ann Rheum Dis. 75:1728–1734. 2016. View Article : Google Scholar : PubMed/NCBI

23 

Wen L, Zhang B, Wu X, Liu R, Fan H, Han L, Zhang Z, Ma X, Chu CQ and Shi X: Toll-like receptors 7 and 9 regulate the proliferation and differentiation of B cells in systemic lupus erythematosus. Front Immunol. 14:10932082023. View Article : Google Scholar : PubMed/NCBI

24 

Schrezenmeier E, Jayne D and Dörner T: Targeting B cells and plasma cells in glomerular diseases: Translational perspectives. J Am Soc Nephrol. 29:741–758. 2018. View Article : Google Scholar : PubMed/NCBI

25 

Flores-Mendoza G, Sansón SP, Rodríguez-Castro S, Crispín JC and Rosetti F: Mechanisms of tissue injury in lupus nephritis. Trends Mol Med. 24:364–378. 2018. View Article : Google Scholar : PubMed/NCBI

26 

Parikh SV, Almaani S, Brodsky S and Rovin BH: Update on lupus nephritis: Core curriculum 2020. Am J Kidney Dis. 76:265–281. 2020. View Article : Google Scholar : PubMed/NCBI

27 

Sharma M, Vignesh P, Tiewsoh K and Rawat A: Revisiting the complement system in systemic lupus erythematosus. Expert Rev Clin Immunol. 16:397–408. 2020. View Article : Google Scholar : PubMed/NCBI

28 

Pavenstädt H, Kriz W and Kretzler M: Cell biology of the glomerular podocyte. Physiol Rev. 83:253–307. 2003. View Article : Google Scholar : PubMed/NCBI

29 

Garg P: A review of podocyte biology. Am J Nephrol. 47 (Suppl 1):S3–S13. 2018. View Article : Google Scholar

30 

Humphries JD, Wang P, Streuli C, Geiger B, Humphries MJ and Ballestrem C: Vinculin controls focal adhesion formation by direct interactions with talin and actin. J Cell Biol. 179:1043–1057. 2007. View Article : Google Scholar : PubMed/NCBI

31 

Sellin L, Huber TB, Gerke P, Quack I, Pavenstädt H and Walz G: NEPH1 defines a novel family of podocin interacting proteins. FASEB J. 17:115–117. 2003. View Article : Google Scholar : PubMed/NCBI

32 

Garg P, Verma R, Nihalani D, Johnstone DB and Holzman LB: Neph1 cooperates with nephrin to transduce a signal that induces actin polymerization. Mol Cell Biol. 27:8698–8712. 2007. View Article : Google Scholar : PubMed/NCBI

33 

Huber TB, Simons M, Hartleben B, Sernetz L, Schmidts M, Gundlach E, Saleem MA, Walz G and Benzing T: Molecular basis of the functional podocin-nephrin complex: Mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains. Hum Mol Genet. 12:3397–3405. 2003. View Article : Google Scholar : PubMed/NCBI

34 

Dryer SE and Reiser J: TRPC6 channels and their binding partners in podocytes: Role in glomerular filtration and pathophysiology. Am J Physiol Renal Physiol. 299:F689–F701. 2010. View Article : Google Scholar : PubMed/NCBI

35 

Ha TS: Roles of adaptor proteins in podocyte biology. World J Nephrol. 2:1–10. 2013. View Article : Google Scholar : PubMed/NCBI

36 

Wang Y, Yu F, Song D, Wang SX and Zhao MH: Podocyte involvement in lupus nephritis based on the 2003 ISN/RPS system: A large cohort study from a single centre. Rheumatology (Oxford). 53:1235–1244. 2014. View Article : Google Scholar : PubMed/NCBI

37 

Banas MC, Banas B, Hudkins KL, Wietecha TA, Iyoda M, Bock E, Hauser P, Pippin JW, Shankland SJ, Smith KD, et al: TLR4 links podocytes with the innate immune system to mediate glomerular injury. J Am Soc Nephrol. 19:704–713. 2008. View Article : Google Scholar : PubMed/NCBI

38 

Li X, Ding F, Zhang X, Li B and Ding J: The expression profile of complement components in podocytes. Int J Mol Sci. 17:4712016. View Article : Google Scholar : PubMed/NCBI

39 

Gao S, Cui Z and Zhao MH: Complement C3a and C3a receptor activation mediates podocyte injuries in the mechanism of primary membranous nephropathy. J Am Soc Nephrol. 33:1742–1756. 2022. View Article : Google Scholar : PubMed/NCBI

40 

Wang H, Lv D, Jiang S, Hou Q, Zhang L, Li S, Zhu X, Xu X, Wen J, Zeng C, et al: Complement induces podocyte pyroptosis in membranous nephropathy by mediating mitochondrial dysfunction. Cell Death Dis. 13:2812022. View Article : Google Scholar : PubMed/NCBI

41 

Pippin JW, Durvasula R, Petermann A, Hiromura K, Couser WG and Shankland SJ: DNA damage is a novel response to sublytic complement C5b-9-induced injury in podocytes. J Clin Invest. 111:877–885. 2003. View Article : Google Scholar : PubMed/NCBI

42 

Appay MD, Kazatchkine MD, Levi-Strauss M, Hinglais N and Bariety J: Expression of CR1 (CD35) mRNA in podocytes from adult and fetal human kidneys. Kidney Int. 38:289–293. 1990. View Article : Google Scholar : PubMed/NCBI

43 

Teixeira JE, Costa RS, Lachmann PJ, Würzner R and Barbosa JE: CR1 stump peptide and terminal complement complexes are found in the glomeruli of lupus nephritis patients. Clin Exp Immunol. 105:497–503. 1996. View Article : Google Scholar : PubMed/NCBI

44 

Moll S, Miot S, Sadallah S, Gudat F, Mihatsch MJ and Schifferli JA: No complement receptor 1 stumps on podocytes in human glomerulopathies. Kidney Int. 59:160–168. 2001. View Article : Google Scholar : PubMed/NCBI

45 

Bao L, Haas M and Quigg RJ: Complement factor H deficiency accelerates development of lupus nephritis. J Am Soc Nephrol. 22:285–295. 2011. View Article : Google Scholar : PubMed/NCBI

46 

Pickering MC, Ismajli M, Condon MB, McKenna N, Hall AE, Lightstone L, Terence Cook H and Cairns TD: Eculizumab as rescue therapy in severe resistant lupus nephritis. Rheumatology (Oxford). 54:2286–2288. 2015.PubMed/NCBI

47 

Coppo R, Peruzzi L, Amore A, Martino S, Vergano L, Lastauka I, Schieppati A, Noris M, Tovo PA and Remuzzi G: Dramatic effects of eculizumab in a child with diffuse proliferative lupus nephritis resistant to conventional therapy. Pediatr Nephrol. 30:167–172. 2015. View Article : Google Scholar : PubMed/NCBI

48 

Patole PS, Pawar RD, Lech M, Zecher D, Schmidt H, Segerer S, Ellwart A, Henger A, Kretzler M and Anders HJ: Expression and regulation of Toll-like receptors in lupus-like immune complex glomerulonephritis of MRL-Fas(lpr) mice. Nephrol Dial Transplant. 21:3062–3073. 2006. View Article : Google Scholar : PubMed/NCBI

49 

Devarapu SK and Anders HJ: Toll-like receptors in lupus nephritis. J Biomed Sci. 25:352018. View Article : Google Scholar : PubMed/NCBI

50 

Kimura J, Ichii O, Miyazono K, Nakamura T, Horino T, Otsuka-Kanazawa S and Kon Y: Overexpression of Toll-like receptor 8 correlates with the progression of podocyte injury in murine autoimmune glomerulonephritis. Sci Rep. 4:72902014. View Article : Google Scholar : PubMed/NCBI

51 

Marshak-Rothstein A and Rifkin IR: Immunologically active autoantigens: The role of toll-like receptors in the development of chronic inflammatory disease. Annu Rev Immunol. 25:419–441. 2007. View Article : Google Scholar : PubMed/NCBI

52 

Anders HJ, Lichtnekert J and Allam R: Interferon-alpha and -beta in kidney inflammation. Kidney Int. 77:848–854. 2010. View Article : Google Scholar : PubMed/NCBI

53 

Machida H, Ito S, Hirose T, Takeshita F, Oshiro H, Nakamura T, Mori M, Inayama Y, Yan K, Kobayashi N and Yokota S: Expression of Toll-like receptor 9 in renal podocytes in childhood-onset active and inactive lupus nephritis. Nephrol Dial Transplant. 25:2530–2537. 2010. View Article : Google Scholar : PubMed/NCBI

54 

Masum MA, Ichii O, Hosny Ali Elewa Y, Nakamura T, Otani Y, Hosotani M and Kon Y: Overexpression of toll-like receptor 9 correlates with podocyte injury in a murine model of autoimmune membranoproliferative glomerulonephritis. Autoimmunity. 51:386–398. 2018. View Article : Google Scholar : PubMed/NCBI

55 

Takano Y, Yamauchi K, Hayakawa K, Hiramatsu N, Kasai A, Okamura M, Yokouchi M, Shitamura A, Yao J and Kitamura M: Transcriptional suppression of nephrin in podocytes by macrophages: Roles of inflammatory cytokines and involvement of the PI3K/Akt pathway. FEBS Lett. 581:421–426. 2007. View Article : Google Scholar : PubMed/NCBI

56 

Zhang Z, Niu L, Tang X, Feng R, Yao G, Chen W, Li W, Feng X, Chen H and Sun L: Mesenchymal stem cells prevent podocyte injury in lupus-prone B6.MRL-Faslpr mice via polarizing macrophage into an anti-inflammatory phenotype. Nephrol Dial Transplant. 34:597–605. 2019. View Article : Google Scholar : PubMed/NCBI

57 

Sung SJ and Fu SM: Interactions among glomerulus infiltrating macrophages and intrinsic cells via cytokines in chronic lupus glomerulonephritis. J Autoimmun. 106:1023312020. View Article : Google Scholar : PubMed/NCBI

58 

Zoja C, Wang JM, Bettoni S, Sironi M, Renzi D, Chiaffarino F, Abboud HE, Van Damme J, Mantovani A, Remuzzi G, et al: Interleukin-1 beta and tumor necrosis factor-alpha induce gene expression and production of leukocyte chemotactic factors, colony-stimulating factors, and interleukin-6 in human mesangial cells. Am J Pathol. 138:991–1003. 1991.PubMed/NCBI

59 

Latz E, Xiao TS and Stutz A: Activation and regulation of the inflammasomes. Nat Rev Immunol. 13:397–411. 2013. View Article : Google Scholar : PubMed/NCBI

60 

Fu R, Guo C, Wang S, Huang Y, Jin O, Hu H, Chen J, Xu B, Zhou M, Zhao J, et al: Podocyte activation of NLRP3 inflammasomes contributes to the development of proteinuria in lupus nephritis. Arthritis Rheumatol. 69:1636–1646. 2017. View Article : Google Scholar : PubMed/NCBI

61 

Guo C, Fu R, Zhou M, Wang S, Huang Y, Hu H, Zhao J, Gaskin F, Yang N and Fu SM: Pathogenesis of lupus nephritis: RIP3 dependent necroptosis and NLRP3 inflammasome activation. J Autoimmun. 103:1022862019. View Article : Google Scholar : PubMed/NCBI

62 

Cai M, Zhou T, Wang X, Shang M, Zhang Y, Luo M, Xu C and Yuan W: DC-SIGN expression on podocytes and its role in inflammatory immune response of lupus nephritis. Clin Exp Immunol. 183:317–325. 2016. View Article : Google Scholar : PubMed/NCBI

63 

Haymann JP, Levraud JP, Bouet S, Kappes V, Hagège J, Nguyen G, Xu Y, Rondeau E and Sraer JD: Characterization and localization of the neonatal Fc receptor in adult human kidney. J Am Soc Nephrol. 11:632–639. 2000. View Article : Google Scholar : PubMed/NCBI

64 

Ichinose K, Ushigusa T, Nishino A, Nakashima Y, Suzuki T, Horai Y, Koga T, Kawashiri SY, Iwamoto N, Tamai M, et al: Lupus Nephritis IgG induction of calcium/calmodulin-dependent protein kinase IV expression in podocytes and alteration of their function. Arthritis Rheumatol. 68:944–952. 2016. View Article : Google Scholar : PubMed/NCBI

65 

Bhargava R, Lehoux S, Maeda K, Tsokos MG, Krishfield S, Ellezian L, Pollak M, Stillman IE, Cummings RD and Tsokos GC: Aberrantly glycosylated IgG elicits pathogenic signaling in podocytes and signifies lupus nephritis. JCI Insight. 6:e1477892021. View Article : Google Scholar : PubMed/NCBI

66 

Bruschi M, Moroni G, Sinico RA, Franceschini F, Fredi M, Vaglio A, Cavagna L, Petretto A, Pratesi F, Migliorini P, et al: Serum IgG2 antibody multi-composition in systemic lupus erythematosus and in lupus nephritis (Part 2): Prospective study. Rheumatology (Oxford). 60:3388–3397. 2021. View Article : Google Scholar : PubMed/NCBI

67 

Mason LJ, Ravirajan CT, Rahman A, Putterman C and Isenberg DA: Is alpha-actinin a target for pathogenic anti-DNA antibodies in lupus nephritis? Arthritis Rheum. 50:866–870. 2004. View Article : Google Scholar : PubMed/NCBI

68 

Renaudineau Y, Deocharan B, Jousse S, Renaudineau E, Putterman C and Youinou P: Anti-alpha-actinin antibodies: A new marker of lupus nephritis. Autoimmun Rev. 6:464–468. 2007. View Article : Google Scholar : PubMed/NCBI

69 

Chen A, Lee K, D'Agati VD, Wei C, Fu J, Guan TJ, He JC, Schlondorff D and Agudo J: Bowman's capsule provides a protective niche for podocytes from cytotoxic CD8+ T cells. J Clin Invest. 128:3413–3424. 2018. View Article : Google Scholar : PubMed/NCBI

70 

Reiser J, von Gersdorff G, Loos M, Oh J, Asanuma K, Giardino L, Rastaldi MP, Calvaresi N, Watanabe H, Schwarz K, et al: Induction of B7-1 in podocytes is associated with nephrotic syndrome. J Clin Invest. 113:1390–1397. 2004. View Article : Google Scholar : PubMed/NCBI

71 

Greka A, Weins A and Mundel P: Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med. 370:1263–1266. 2014.PubMed/NCBI

72 

Khullar B, Balyan R, Oswal N, Jain N, Sharma A, Abdin MZ, Bagga A, Bhatnagar S, Wadhwa N, Natchu UCM, et al: Interaction of CD80 with Neph1: A potential mechanism of podocyte injury. Clin Exp Nephrol. 22:508–516. 2018. View Article : Google Scholar : PubMed/NCBI

73 

Coers W, Brouwer E, Vos JT, Chand A, Huitema S, Heeringa P, Kallenberg CG and Weening JJ: Podocyte expression of MHC class I and II and intercellular adhesion molecule-1 (ICAM-1) in experimental pauci-immune crescentic glomerulonephritis. Clin Exp Immunol. 98:279–286. 1994. View Article : Google Scholar : PubMed/NCBI

74 

Goldwich A, Burkard M, Olke M, Daniel C, Amann K, Hugo C, Kurts C, Steinkasserer A and Gessner A: Podocytes are nonhematopoietic professional antigen-presenting cells. J Am Soc Nephrol. 24:906–916. 2013. View Article : Google Scholar : PubMed/NCBI

75 

Li S, Liu Y, He Y, Rong W, Zhang M, Li L, Liu Z and Zen K: Podocytes present antigen to activate specific T cell immune responses in inflammatory renal disease. J Pathol. 252:165–177. 2020. View Article : Google Scholar : PubMed/NCBI

76 

Okamoto A, Fujio K, Tsuno NH, Takahashi K and Yamamoto K: Kidney-infiltrating CD4+ T-cell clones promote nephritis in lupus-prone mice. Kidney Int. 82:969–979. 2012. View Article : Google Scholar : PubMed/NCBI

77 

May CJ, Welsh GI, Chesor M, Lait PJ, Schewitz-Bowers LP, Lee RWJ and Saleem MA: Human Th17 cells produce a soluble mediator that increases podocyte motility via signaling pathways that mimic PAR-1 activation. Am J Physiol Renal Physiol. 317:F913–F921. 2019. View Article : Google Scholar : PubMed/NCBI

78 

Cheng Y, Yang X, Zhang X and An Z: Analysis of expression levels of IL-17 and IL-34 and influencing factors for prognosis in patients with lupus nephritis. Exp Ther Med. 17:2279–2283. 2019.PubMed/NCBI

79 

Wang N, Gao C, Cui S, Qin Y, Zhang C, Yi P, Di X, Liu S, Li T, Gao G and Zheng Z: Induction therapy downregulates the expression of Th17/Tfh cytokines in patients with active lupus nephritis. Am J Clin Exp Immunol. 7:67–75. 2018.PubMed/NCBI

80 

Yan J, Li Y, Yang H, Zhang L, Yang B, Wang M and Li Q: Interleukin-17A participates in podocyte injury by inducing IL-1β secretion through ROS-NLRP3 inflammasome-caspase-1 pathway. Scand J Immunol. 87:e126452018. View Article : Google Scholar : PubMed/NCBI

81 

Yuan DH, Jia Y, Hassan OM, Xu LY and Wu XC: LPS-Treated podocytes polarize naive CD4(+) T Cells into Th17 and treg cells. Biomed Res Int. 2020:85879232020. View Article : Google Scholar : PubMed/NCBI

82 

Chang A, Henderson SG, Brandt D, Liu N, Guttikonda R, Hsieh C, Kaverina N, Utset TO, Meehan SM, Quigg RJ, et al: In situ B cell-mediated immune responses and tubulointerstitial inflammation in human lupus nephritis. J Immunol. 186:1849–1860. 2011. View Article : Google Scholar : PubMed/NCBI

83 

Tsokos GC: Autoimmunity and organ damage in systemic lupus erythematosus. Nat Immunol. 21:605–614. 2020. View Article : Google Scholar : PubMed/NCBI

84 

Kolovou K, Laskari K, Roumelioti M, Tektonidou MG, Panayiotidis P, Boletis JN, Marinaki S and Sfikakis PP: B-cell oligoclonal expansions in renal tissue of patients with immune-mediated glomerular disease. Clin Immunol. 217:1084882020. View Article : Google Scholar : PubMed/NCBI

85 

Senaldi G, Stolina M, Guo J, Faggioni R, McCabe S, Kaufman SA, Van G, Xu W, Fletcher FA, Boone T, et al: Regulatory effects of novel neurotrophin-1/b cell-stimulating factor-3 (cardiotrophin-like cytokine) on B cell function. J Immunol. 168:5690–5698. 2002. View Article : Google Scholar : PubMed/NCBI

86 

Schmidt-Ott KM, Yang J, Chen X, Wang H, Paragas N, Mori K, Li JY, Lu B, Costantini F, Schiffer M, et al: Novel regulators of kidney development from the tips of the ureteric bud. J Am Soc Nephrol. 16:1993–2002. 2005. View Article : Google Scholar : PubMed/NCBI

87 

Savin VJ, Sharma M, Zhou J, Gennochi D, Fields T, Sharma R, McCarthy ET, Srivastava T, Domen J, Tormo A and Gauchat JF: Renal and Hematological Effects of CLCF-1, a B-Cell-Stimulating Cytokine of the IL-6 Family. J Immunol Res. 2015:7149642015. View Article : Google Scholar : PubMed/NCBI

88 

Dos Santos M, Poletti PT, Milhoransa P, Monticielo OA and Veronese FV: Unraveling the podocyte injury in lupus nephritis: Clinical and experimental approaches. Semin Arthritis Rheum. 46:632–641. 2017. View Article : Google Scholar : PubMed/NCBI

89 

Andrews BS, Eisenberg RA, Theofilopoulos AN, Izui S, Wilson CB, McConahey PJ, Murphy ED, Roths JB and Dixon FJ: Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med. 148:1198–1215. 1978. View Article : Google Scholar : PubMed/NCBI

90 

McGaha TL and Madaio MP: Lupus Nephritis: Animal modeling of a complex disease syndrome pathology. Drug Discov Today Dis Models. 11:13–18. 2014. View Article : Google Scholar : PubMed/NCBI

91 

Pawar RD, Castrezana-Lopez L, Allam R, Kulkarni OP, Segerer S, Radomska E, Meyer TN, Schwesinger CM, Akis N, Gröne HJ and Anders HJ: Bacterial lipopeptide triggers massive albuminuria in murine lupus nephritis by activating Toll-like receptor 2 at the glomerular filtration barrier. Immunology. 128 (1 Suppl):e206–e221. 2009. View Article : Google Scholar : PubMed/NCBI

92 

Maibaum MA, Haywood ME, Walport MJ and Morley BJ: Lupus susceptibility loci map within regions of BXSB derived from the SB/Le parental strain. Immunogenetics. 51:370–372. 2000. View Article : Google Scholar : PubMed/NCBI

93 

Pisitkun P, Deane JA, Difilippantonio MJ, Tarasenko T, Satterthwaite AB and Bolland S: Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science. 312:1669–1672. 2006. View Article : Google Scholar : PubMed/NCBI

94 

Jayne D, Rovin B, Mysler EF, Furie RA, Houssiau FA, Trasieva T, Knagenhjelm J, Schwetje E, Chia YL, Tummala R and Lindholm C: Phase II randomised trial of type I interferon inhibitor anifrolumab in patients with active lupus nephritis. Ann Rheum Dis. 81:496–506. 2022. View Article : Google Scholar : PubMed/NCBI

95 

Parodis I and Houssiau FA: From sequential to combination and personalised therapy in lupus nephritis: Moving towards a paradigm shift? Ann Rheum Dis. 81:15–19. 2022. View Article : Google Scholar : PubMed/NCBI

96 

Steiger S, Ehreiser L, Anders J and Anders HJ: Biological drugs for systemic lupus erythematosus or active lupus nephritis and rates of infectious complications. Evidence from large clinical trials. Front Immunol. 13:9997042022. View Article : Google Scholar : PubMed/NCBI

97 

Markowitz GS, Nasr SH, Stokes MB and D'Agati VD: Treatment with IFN-{alpha}, -{beta}, or -{gamma} is associated with collapsing focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 5:607–615. 2010. View Article : Google Scholar : PubMed/NCBI

98 

Liao R, Liu Q, Zheng Z, Fan J, Peng W, Kong Q, He H, Yang S, Chen W, Tang X and Yu X: Tacrolimus protects podocytes from injury in lupus nephritis partly by stabilizing the cytoskeleton and inhibiting podocyte apoptosis. PLoS One. 10:e1327242015. View Article : Google Scholar

99 

Yasuda H, Fukusumi Y, Ivanov V, Zhang Y and Kawachi H: Tacrolimus ameliorates podocyte injury by restoring FK506 binding protein 12 (FKBP12) at actin cytoskeleton. FASEB J. 35:e219832021. View Article : Google Scholar : PubMed/NCBI

100 

Lee J, Park Y, Jang SG, Hong SM, Song YS, Kim MJ, Baek S, Park SH and Kwok SK: Baricitinib attenuates autoimmune phenotype and podocyte injury in a murine model of systemic lupus erythematosus. Front Immunol. 12:7045262021. View Article : Google Scholar : PubMed/NCBI

101 

Rice WL, Van Hoek AN, Păunescu TG, Huynh C, Goetze B, Singh B, Scipioni L, Stern LA and Brown D: High resolution helium ion scanning microscopy of the rat kidney. PLoS One. 8:e570512013. View Article : Google Scholar : PubMed/NCBI

102 

Howie JB and Helyer BJ: The immunology and pathology of NZB mice. Adv Immunol. 9:215–266. 1968. View Article : Google Scholar : PubMed/NCBI

103 

Hall AM, Ward FJ, Shen CR, Rowe C, Bowie L, Devine A, Urbaniak SJ, Elson CJ and Barker RN: Deletion of the dominant autoantigen in NZB mice with autoimmune hemolytic anemia: Effects on autoantibody and T-helper responses. Blood. 110:4511–4517. 2007. View Article : Google Scholar : PubMed/NCBI

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Liu R, Wen X, Peng X, Zhao M, Mi L, Lei J and Xu K: Immune podocytes in the immune microenvironment of lupus nephritis (Review). Mol Med Rep 28: 204, 2023.
APA
Liu, R., Wen, X., Peng, X., Zhao, M., Mi, L., Lei, J., & Xu, K. (2023). Immune podocytes in the immune microenvironment of lupus nephritis (Review). Molecular Medicine Reports, 28, 204. https://doi.org/10.3892/mmr.2023.13091
MLA
Liu, R., Wen, X., Peng, X., Zhao, M., Mi, L., Lei, J., Xu, K."Immune podocytes in the immune microenvironment of lupus nephritis (Review)". Molecular Medicine Reports 28.5 (2023): 204.
Chicago
Liu, R., Wen, X., Peng, X., Zhao, M., Mi, L., Lei, J., Xu, K."Immune podocytes in the immune microenvironment of lupus nephritis (Review)". Molecular Medicine Reports 28, no. 5 (2023): 204. https://doi.org/10.3892/mmr.2023.13091