Cross-species single-cell analysis uncovers the immunopathological mechanisms associated with IgA nephropathy progression.

IgA nephropathy (IgAN) represents the main cause of renal failure, while the precise pathogenetic mechanisms have not been fully determined. Herein, we conducted a cross-species single-cell survey on human IgAN and mouse and rat IgAN models to explore the pathogenic programs. Cross-species single-cell RNA sequencing (scRNA-Seq) revealed that the IgAN mesangial cells (MCs) expressed high levels of inflammatory signatures CXCL12, CCL2, CSF1, and IL-34 and specifically interacted with IgAN macrophages via the CXCL12/CXCR4, CSF1/IL-34/CSF1 receptor, and integrin subunit alpha X/integrin subunit alpha M/complement C3 (C3) axes. IgAN macrophages expressed high levels of CXCR4, PDGFB, triggering receptor expressed on myeloid cells 2, TNF, and C3, and the trajectory analysis suggested that these cells derived from the differentiation of infiltrating blood monocytes. Additionally, protein profiling of 21 progression and 28 nonprogression IgAN samples revealed that proteins CXCL12, C3, mannose receptor C-type 1, and CD163 were negatively correlated with estimated glomerular filtration rate (eGFR) value and poor prognosis (30% eGFR as composite end point). Last, a functional experiment revealed that specific blockade of the Cxcl12/Cxcr4 pathway substantially attenuated the glomerulus and tubule inflammatory injury, fibrosis, and renal function decline in the mouse IgAN model. This study provides insights into IgAN progression and may aid in the refinement of IgAN diagnosis and the optimization of treatment strategies.

Sublytic C5b-9 induces glomerular mesangial cell proliferation via ERK1/2-dependent SOX9 phosphorylation and acetylation by enhancing Cyclin D1 in rat Thy-1 nephritis.

Glomerular mesangial cell (GMC) proliferation is a histopathological alteration in human mesangioproliferative glomerulonephritis (MsPGN) or in animal models of MsPGN, e.g., the rat Thy-1 nephritis (Thy-1N) model. Although sublytic C5b-9 assembly on the GMC membrane can trigger cell proliferation, the mechanisms are still undefined. We found that sublytic C5b-9-induced rat GMC proliferation was driven by extracellular signal-regulated kinase 1/2 (ERK1/2), sry-related HMG-box 9 (SOX9), and Cyclin D1. Here, ERK1/2 phosphorylation was a result of the calcium influx-PKC-α-Raf-MEK1/2 axis activated by sublytic C5b-9, and Cyclin D1 gene transcription was enhanced by ERK1/2-dependent SOX9 binding to the Cyclin D1 promoter (-582 to -238 nt). In addition, ERK1/2 not only interacted with SOX9 in the cell nucleus to mediate its phosphorylation at serine residues 64 (a new site identified by mass spectrometry) and 181 (a known site), but also indirectly induced SOX9 acetylation by elevating the expression of general control non-repressed protein 5 (GCN5), which together resulted in Cyclin D1 synthesis and GMC proliferation. Moreover, our in vivo experiments confirmed that silencing these genes ameliorated the lesions of Thy-1N rats and reduced SOX9 phosphorylation, acetylation and Cyclin D1 expression. Furthermore, the renal tissue sections of MsPGN patients also showed higher phosphorylation or expression of ERK1/2, SOX9, and Cyclin D1. In summary, these findings suggest that sublytic C5b-9-induced GMC proliferation in rat Thy-1N requires SOX9 phosphorylation and acetylation via enhanced Cyclin D1 gene transcription, which may provide a new insight into human MsPGN pathogenesis.

Renal deposition and clearance of recombinant poly-IgA complexes in a model of IgA nephropathy.

IgA nephropathy (IgAN) is the most common type of glomerulonephritis worldwide, which follows a chronic but nonetheless highly variable course of progression. IgA immune complexes are the primary source of renal deposits in IgAN. Apart from the presence of granular IgA1 deposits in the glomerular mesangium and mesangial hypercellularity as common features, the detailed process of IgA1 deposition and clearance in the kidney remains unclear. We sought to examine the dynamics of IgA deposition and tissue plasticity in response to deposits including their intrarenal clearance. We followed a synthetic approach to produce a recombinant fusion between IgA Fc (rIgA) and a biotin tag, which was subsequently induced with streptavidin (SA) to form an oligomeric poly-IgA mimic. Both uninduced rIgA (mono-rIgA) and polymeric SA-rIgA (poly-rIgA) were injected intravenously into Wistar rats. Plasma IgA levels and renal and liver histology were examined in a time series. In contrast to mono-rIgA, this synthetic poly-rIgA analog formed renal deposits exclusively in the glomerulus and were mostly cleared in 3 h. However, repeated daily injections for 12 days caused long-lasting and stronger glomerular IgA deposition together with IgG and complement C3, in association with mesangial cell proliferation, matrix expansion, and variable degrees of albuminuria and hematuria that phenocopied IgAN. Ex vivo, poly-rIgA bound cultured mesangial cells and elicited cytokine production, in addition to activating plasma C3 that was consistent with the actions of IgA immune complexes in IgAN pathogenesis. Remarkably, the kidneys were able to reverse all pathologic manifestations and restore normal glomerular histology 2 weeks after injections were halted. The synthetic model showed the kinetics between the intricate balance of renal deposition and clearance, as well as glomerular plasticity towards healing. Together, the results revealed a priming effect of existing deposits in promoting stronger and longer-lasting IgA deposition to cause renal damage. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Mesangial C3 deposition and serum C3 levels predict renal outcome in IgA nephropathy.

BACKGROUND: Complement activation plays an important role in the pathogenesis of IgA nephropathy (IgAN). We aimed to evaluate the relationship between mesangial C3 deposition and histologic lesions and to investigate the role of mesangial C3 deposition and serum C3 reduction in predicting renal outcome in IgAN children. METHODS: We performed a retrospective cohort study in children with biopsy-proven IgAN. Mesangial C3 deposition (< 2+ vs. ≥ 2+) was detected by the immunofluorescence. Histopathologic kidney grades were determined by the Oxford classification. A decreased serum C3 concentration (hypoC3) was defined when C3 < 90 mg/dl. The endpoint was composite kidney outcome with either a 30% decline in glomerular filtration rates from baseline or kidney failure during the follow-up period. RESULTS: A total of 98 children were analyzed. Mesangial hypercellularity (M) was an independent factor associated with mesangial C3 deposition (HR 3.267; 95% CI 1.028-10.389; P = 0.045). After a median follow-up period of 25 months (interquartile range 18-36 months), 6 (6.1%) children reached the endpoint. Compared with other children, a significantly higher proportion of children with composite kidney outcomes had mesangial C3 deposition ≥ 2+ and hypoC3 (3.4% versus 27.3%, P = 0.002). After adjustment for clinicopathologic risk factors, mesangial C3 deposition ≥ 2+ and hypoC3 were associated with renal outcome (HR 9.772; 95% CI 1.264-75.518; P = 0.029). CONCLUSION: Mesangial C3 deposition was associated with M in IgAN. Mesangial C3 deposition and hypoC3 were risk factors for renal outcome in children with IgAN.

Activated mesangial cells acquire the function of antigen presentation.

Mesangial cells (MCs), as resident cells of the kidneys, play an important role in maintaining glomerular function. MCs are located between the capillary loops of the glomeruli and mainly support the capillary plexus, constrict blood vessels, extracellular matrix components, produce cytokines, and perform phagocytosis and clearance of macromolecular substances. When the glomerular environment changes, MCs are often affected, which can lead to functional transformation. The immune response is involved in the occurrence and development of various kidney diseases, in these diseases, antigen-presenting cells (APCs) play an important role. APCs can present antigens to T lymphocytes, causing them to become activated and proliferate. Studies have shown that MCs have phagocytic function and express APC markers on the cell surface. Additionally, MCs are stimulated by or produce various inflammatory factors to participate in the renal inflammatory response. Therefore, MCs have potential antigen presentation function and participate in the pathological changes of various kidney diseases as APCs upon activation. In this paper, by reviewing MC phagocytic function, activated MC expression of APC surface markers, and MC participation in the inflammatory response and local renal immune response, we confirm that activated MCs can act as APCs in renal disease.

MicroRNA-16 directly binds to DEC2 and inactivates the TLR4 signaling pathway to inhibit lupus nephritis-induced kidney tissue hyperplasia and mesangial cell proliferation.

Lupus nephritis (LN) is the most serious manifestation of systemic lupus erythematosus (SLE) and a major risk of mortality. This research focused on the function of microRNA-16 (miR-16) in LN development. Fcgamma receptor II-b-deficient (Fcgr2b-/-) mice with the natural potential to develop SLE- and LN-like diseases were used. Gain- and loss-of-function studies were performed to explore the function of miR-16 in pathological symptoms in mouse kidney tissues and the proliferation of mesangial cells (SV40 MES-13). The putative downstream molecules of miR-16 were explored. Consequently, poor expression of miR-16 was found in kidney tissues. Upregulation of miR-16 inhibited tissue hyperplasia, inflammatory infiltration, glomerular injury and fibrosis but increased cell apoptosis in mouse kidney tissues, and it inhibited proliferation but promoted apoptosis of MES-13 cells as well. miR-16 directly bound to DEC2 and inactivated the TLR4 signaling. DEC2 blocked the protective roles of miR-16 in MES-13 cells. The enhanced proliferation in MES-13 cells following miR-16 inhibition was reversed by chloroquine phosphate, a TLR4 antagonist. To sum up, miR-16 was evidenced to have a potent protective capacity in LN through relieving the LN symptoms in kidney tissues and reducing proliferation of mesangial cells, during which DEC2 silencing and TLR4 signaling deficit were involved.

Interleukin-1ß Promotes Ox-LDL Uptake by Human Glomerular Mesangial Cells via LOX-1.

The aim of this study was to determine whether interleukin-1ß (IL-1ß) promotes oxidised low-density lipoprotein (Ox-LDL) uptake by human glomerular mesangial cells (HMCs) and its effect on the expression of lectin-like Ox-LDL receptor 1 (LOX-1) and to identify pathways through which IL-1ß affects lipid uptake. Confocal laser scanning microscopy and flow cytometry were used to observe the effect of IL-1ß on lipid uptake by HMCs and the pathway by which IL-1ß may mediate lipid uptake. Real-time polymerase chain reaction (PCR) and western blotting were used to evaluate the effect of IL-1ß on LOX-1 expression. Confocal laser scanning microscopy and flow cytometry revealed that IL-1ß promoted uptake of fluorescent Dil-labelled Ox-LDL(Dil-Ox-LDL) by HMCs and the enhanced uptake of Dil-Ox-LDL was partially inhibited by an anti-LOX-1 antibody evaluated by flow cytometry. Further, IL-1ß promoted LOX-1 mRNA and protein expression of HMCs in a dose- and time-dependent manner. Thus, Ox-LDL is ingested by HMCs under basic conditions. Inflammatory cytokine IL-1ß promotes Ox-LDL uptake by HMCs. Furthermore, IL-1ß promotes the mRNA and protein expression of LOX-1, a specific receptor of Ox-LDL, suggesting that the enhancement of Ox-LDL uptake may be mediated by LOX-1 pathway. Anti-LOX-1 therapy may be a promising option for treatment of glomerulosclerosis.

Food antigens and Transglutaminase 2 in IgA nephropathy: Molecular links between gut and kidney.

The transglutaminase 2 (TG2) is one of the enigmatic enzymes with important functional diversity. It plays an important role in several pathologies such as celiac disease (CD). In patients with active CD, the abnormal retrotranscytosis of IgA/gliadin complexes is mediated by Transferrin Receptor 1 (TfR1). This triad association takes also place in IgA nephropathy (IgA-N). IgA-N is characterized by the formation of nephrotoxic complexes of IgA1 and soluble CD89 (sCD89). These complexes are abnormally deposited in the kidney. Using a humanized mouse model of IgA-N (α1KI-CD89Tg), we showed that IgA1-sCD89 complexes engender mesangial cell activation and proliferation with TfR1 and TG2 up-regulation, associated with IgA-N features. This TG2-TfR1 interaction enhances mesangial IgA1 deposition promoting inflammation. Humanized α1KI-CD89Tg mice deficient for TG2 show a decrease in TfR1 expression in kidney leading to reduced IgA1-sCD89 deposits and an improvement in IgA-N features. Moreover, TG2 is active and overexpressed in the intestine of IgA-N mice and gliadin participates to this renal pathology. In kidney as in intestine, the TG2 has a crucial role in the cooperation between TfR1-IgA and a central role in the pathogenic amplification.

Interferon lambda promotes immune dysregulation and tissue inflammation in TLR7-induced lupus.

Type III IFN lambdas (IFN-λ) have recently been described as important mediators of immune responses at barrier surfaces. However, their role in autoimmune diseases such as systemic lupus erythematosus (SLE), a condition characterized by aberrant type I IFN signaling, has not been determined. Here, we identify a nonredundant role for IFN-λ in immune dysregulation and tissue inflammation in a model of TLR7-induced lupus. IFN-λ protein is increased in murine lupus and IFN-λ receptor (Ifnlr1) deficiency significantly reduces immune cell activation and associated organ damage in the skin and kidneys without effects on autoantibody production. Single-cell RNA sequencing in mouse spleen and human peripheral blood revealed that only mouse neutrophils and human B cells are directly responsive to this cytokine. Rather, IFN-λ activates keratinocytes and mesangial cells to produce chemokines that induce immune cell recruitment and promote tissue inflammation. These data provide insights into the immunobiology of SLE and identify type III IFNs as important factors for tissue-specific pathology in this disease.

Autophagy in Immune-Related Renal Disease.

Autophagy is an important biology process, central to the maintenance of biology process in both physiological and pathological situations. It is regarded as a "double-edged sword"-exerting both protective and/or detrimental effects. These two-way effects are observed in immune cells as well as renal resident cells, including podocytes, mesangial cells, tubular epithelial cells, and endothelial cells of the glomerular capillaries. Mounting evidence suggests that autophagy is implicated in the pathological process of various immune-related renal diseases (IRRDs) as well as the kidney that underwent transplantation. Here, we provide an overview of the pathological role of autophagy in IRRDs, including lupus nephritis, IgA nephropathy, membrane nephropathy, ANCA-associated nephritis, and diabetic nephropathy. The understanding of the pathogenesis and regulatory mechanisms of autophagy in these renal diseases may lead to the identification of new diagnostic targets and refined therapeutic modulation.

Wnt pathway regulates IL-34 level in lupus nephritis.

OBJECTIVE: The aim of this study was to investigate the role of the Wnt pathway in regulating the IL-34 level of lupus nephritis (LN) patients, and to explore the underlying mechanism. MATERIALS AND METHODS: Human mesangial cells (HMCs) of LN patients were selected. The expression level of IL-34 was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and Western blot, respectively. Subsequently, HMCs were treated with the Wnt pathway antagonist, DDK1. Meanwhile, the IL-34 level in DDK1 transfected HMCs was then detected. In addition, the viability of HMCs treated with DDK1 was detected by cell counting kit-8 (CCK-8) and colony formation assay, respectively. RESULTS: Both the mRNA and protein levels of IL-34 were significantly upregulated in HMCs of LN patients. Higher expression of ß-catenin was observed in HMCs of LN patients than those of controls, which was reduced after DDK1 treatment. Meanwhile, IL-34 level in HMCs of LN patients was significantly downregulated after DDK1 treatment. In addition, DDK1 treatment remarkably increased the proliferative ability and colony formation ability of HMCs in LN patients. CONCLUSIONS: IL-34 is highly expressed in HMCs of LN patients and is negatively regulated by the Wnt pathway. Furthermore, HMCs viability is remarkably enhanced after blocking the Wnt pathway.

Mesangial Cells Exhibit Features of Antigen-Presenting Cells and Activate CD4+ T Cell Responses.

BACKGROUND: Mesangial cells play a prominent role in the development of inflammatory diseases and autoimmune disorders of the kidney. Mesangial cells perform the essential functions of helping to ensure that the glomerular structure is stable and regulating capillary flow, and activated mesangial cells acquire proinflammatory activities. We investigated whether activated mesangial cells display immune properties and control the development of T cell immunity. METHODS: Flow cytometry analysis was used to study the expression of antigen-presenting cell surface markers and costimulatory molecules in mesangial cells. CD4+ T cell activation induced by mesangial cells was detected in terms of T cell proliferation and cytokine production. RESULTS: IFN-γ-treated mesangial cells express membrane proteins involved in antigen presentation and T cell activation, including MHC-II, ICAM-1, CD40, and CD80. This finding suggests that activated mesangial cells can take up and present antigenic peptides to initiate CD4+ T cell responses and thus act as nonprofessional antigen-presenting cells. Polarization of naïve CD4+ T cells (Th0 cells) towards the Th1 phenotype was induced by coculture with activated mesangial cells, and the resulting Th1 cells showed increased mRNA and protein expression of inflammation-associated genes. CONCLUSION: Mesangial cells can present antigen and modulate CD4+ T lymphocyte proliferation and differentiation. Interactions between mesangial cells and T cells are essential for sustaining the inflammatory response in a variety of glomerulonephritides. Therefore, mesangial cells might participate in immune function in the kidney.

Respiratory Syncytial Virus Exacerbates Kidney Damages in IgA Nephropathy Mice via the C5a-C5aR1 Axis Orchestrating Th17 Cell Responses.

Respiratory viral infections can directly lead to kidney damage such as IgA nephropathy (IgAN), partly due to mucosal immune system dysfunction. Although the activated C5a-C5aR1 axis results in increased Th1 and Th17 frequencies but reduced Treg frequencies in Respiratory syncytial virus (RSV) infection, how this axis affects Th cell disorders in RSV-induced IgAN exacerbation remains unknown. Here, we used a mouse model to dissect the activation of C5a-C5aR1 by RSV and the consequences on the regulation of Th1, Th17, and Treg immune responses in IgA nephropathy. RSV fusion protein was clearly deposited not only in the pulmonary interstitium but also in the glomerulus in RSV-IgAN mice, and RSV infection led to more severe pathological changes in the kidneys in IgAN mice. Blocking the C5a-C5aR1 axis resulted in a decrease in the albumin-to-creatinine ratio, and the attenuation of kidney damage in IgAN and RSV-IgAN mice might be partly attributed to the inhibition of Th cell and cytokine dysfunction. Th1, Th17 and Treg immune responses and their corelative cytokines were disrupted by RSV infection and rescued by C5aR1 inhibition. Moreover, we constructed a coculture system of human mesangial cells and CD4+ T cells and found that RSV infection might lead to CD4+ T cell production via human mesangial cells-enhanced CD4+ T cell proliferation, consequently increasing IL-17 levels. These pathological behaviors were augmented by C5a stimulation and decreased by C5aR1 inhibition. Thus, C5aR1 inhibition alters both kidney damage and Th1, Th17, and Treg cell dysfunction in RSV-induced IgAN exacerbation and locally regulates HMC antigen presentation function in the kidney. Taken together, our data offer profound evidence that blocking the C5a-C5aR1 axis might be a potential therapy for RSV-induced IgAN.

Is immunoglobulin A nephropathy different in different ethnic populations?

Immunoglobulin A nephropathy (IgAN) is one of the commonest global patterns of primary glomerulonephritis and remains a leading cause of chronic kidney disease and end-stage renal disease. The sole diagnostic criterion of IgAN remains the presence of dominant mesangial immunoglobulin A deposits on kidney biopsy. Beyond this defining feature, there is significant heterogeneity in the epidemiology, clinical presentation, renal progression and long-term outcomes of IgAN in different ethnic populations. Mirroring this heterogeneity in clinical phenotypes, there is also marked ethnic variation in the extent of histopathological lesions observed on kidney biopsy, which may partly explain the well-documented differences in response to immunomodulatory agents reported in different regions of the world. In parallel, disparities have been identified in genetic association studies and key pathogenic pathways in different ethnic populations. Understanding the basis for these differences in IgAN has important implications for both clinical care and future research. In this review, we will examine the impact of ethnicity on the epidemiology, clinical presentation and outcomes, pathogenesis and genetic associations in IgAN.

Coreopsis tinctoria Nutt ameliorates high glucose-induced renal fibrosis and inflammation via the TGF-ß1/SMADS/AMPK/NF-κB pathways.

BACKGROUND: Coreopsis tinctoria Nutt is an ethnomedicine widely used in Xinjiang, China. It is consumed as a herbal tea by local Uyghur people to treat high blood pressure and diarrhea. Our previous study confirmed that the ethyl acetate extract of Coreopsis tinctoria (AC) had a protective effect on diabetic nephropathy (DN) in an in vivo experiment. Here we aim to elucidate the protective mechanism of AC and marein, the main ingredient in Coreopsis tinctoria on renal fibrosis and inflammation in vitro under high glucose (HG) conditions. METHODS: A HG-induced barrier dysfunction model in rat mesangial cells (HBZY-1) was established. The cells were exposed to AC and marein and/or HG for 24 h. Then, the renal protective effects of AC and marein via transforming growth factor-ß1 (TGF-ß1)/Smads, AMP-activated kinase protein (AMPK), and nuclear factor kappa beta (NF-κB) signaling were assessed. RESULTS: Both AC and marein suppressed rat mesangial cell hyperplasia and significantly attenuated the expression of HG-disrupted fibrotic and inflammatory proteins in HBZY-1 cells. It was also confirmed that AC and marein remarkably attenuated HG-induced renal inflammation and fibrosis by regulating the AMPK, TGF-ß1/Smads, and NF-κB signaling pathways. CONCLUSION: These results indicated that AC and marein may delay the progression of DN, at least in part, by suppressing HG-induced renal inflammation and fibrosis. Marein may be one of the bioactive compounds in AC.

Nobiletin suppresses high-glucose-induced inflammation and ECM accumulation in human mesangial cells through STAT3/NF-κB pathway.

Diabetic nephropathy (DN) is a complication of chronic diabetes and the main cause of end-stage renal disease all over the world. Inflammation and extracellular matrix (ECM) accumulation play important roles in the pathogenesis of DN. Evidence suggested that nobiletin acts anti-inflammatory role and plays a critical role in diabetes; however, its role in DN remains unclear. In the current study, we promulgated the nobiletin involved in high-glucose-induced glomerular mesangial cell inflammation and ECM accumulation. Nobiletin treatment significantly abrogated high-glucose-induced glomerular mesangial cell proliferation. Nobiletin treatment markedly suppressed inflammation cytokine secretion, including interleukin (IL)-1ß, IL-6, tumor necrosis factor α, and monocyte chemoattractant protein 1 in high-glucose-induced glomerular mesangial cell. Also, exposed nobiletin to high-glucose-induced glomerular mesangial cell considerably reduced ECM accumulation through inhibited ECM-associated protein type 4 collagen and fibronectin expression. Furthermore, nobiletin treatment abolished nuclear factor κB (NF-κB) pathway activation through signal transducer and activator of transcription 3 (STAT3) inhibition. Overexpression STAT3 reversed the effects of nobiletin on high-glucose-induced glomerular mesangial cell proliferation, inflammation, ECM accumulation, and NF-κB pathway activation. Hence, our results suggest that nobiletin play roles in high-glucose-induced glomerular mesangial cells through inhibiting inflammation and ECM accumulation, and the STAT3/NF-κB pathway was involved in the function of nobiletin.

Carbohydrate response element binding protein (ChREBP) modulates the inflammatory response of mesangial cells in response to glucose.

Diabetic nephropathy (DN) is one of the most devastating complications of diabetes mellitus. Carbohydrate response element binding protein (ChREBP) is a basic helix-loop-helix leucine zipper transcription factor that primarily mediates glucose homeostasis in the body. The present study investigated the role of ChREBP in the pathogenesis of DN. The expression of ChREBP was detected in patients with type 2 diabetes mellitus (T2DM), diabetic mice, and mesangial cells. ELISA was used to measure cytokine production in mesangial cells. Flow cytometry analysis was performed to detect the apoptosis of mesangial cells in the presence of high glucose. The expression levels of ChREBP and several cytokines (TNF-α, IL-1ß, and IL-6) were up-regulated in T2DM patients. The mRNA and protein levels of ChREBP were also significantly elevated in the kidneys of diabetic mice. Moreover, glucose treatment promoted mRNA levels of TNF-α, IL-1ß, and IL-6 in mesangial cells. Glucose stimulation induced significant apoptosis of SV40 MES 13 cells. In addition, transfection with ChREBP siRNA significantly inhibited ChREBP expression. Consequently, the inflammatory responses and apoptosis were inhibited in SV40 MES 13 cells. These results demonstrated that ChREBP could mediate the inflammatory response and apoptosis of mesangial cells, suggesting that ChREBP may be involved in the pathogenesis of DN.

Suppressor of Cytokine Signaling-1/STAT1 Regulates Renal Inflammation in Mesangial Proliferative Glomerulonephritis Models.

Mesangial proliferative glomerulonephritis (MsGN) is a significant global threat to public health. Inflammation plays a crucial role in MsGN; however, the underlying mechanism remains unknown. Herein, we demonstrate that suppression of the cytokine signaling-1 (SOCS1)/signal transducer and activator of transcription 1 (STAT1) signaling pathway is associated with renal inflammation and renal injury in MsGN. Using MsGN rat (Thy1.1 GN) and mouse (Habu GN) models, renal SOCS1/STAT1 was determined to be associated with CD4+ T cell infiltration and related cytokines. In vitro, SOCS1 overexpression repressed IFN-γ-induced MHC class II and cytokine levels and STAT1 phosphorylation in mesangial cells. SOCS1 and STAT1 inhibitors significantly inhibited IFN-γ-induced CIITA promoter activity and MHC class II expression. In conclusion, our study emphasizes the pivotal role of the SOCS1/STAT1 axis in the regulation of inflammation in MsGN.