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Hui Lan

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Kansas State University

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University Of Medicine And Pharmacy Timisoara

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University College Cork

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New England Complex Systems Institute

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Papers by Hui Lan

Hypermethylation of Smad7 in CD4+ T cells is associated with the disease activity of rheumatoid arthritis

Frontiers in Immunology

BackgroundSmad7 is protective in a mouse model of rheumatoid arthritis. Here we investigated whet... more BackgroundSmad7 is protective in a mouse model of rheumatoid arthritis. Here we investigated whether Smad7-expressing CD4+ T cells and the methylation of Smad7 gene in CD4+ T cells contribute to the disease activity of RA in patients.MethodsPeripheral CD4+ T cells were collected from 35 healthy controls and 57 RA patients. Smad7 expression by CD4+ T cells were determined and correlated with the clinical parameters of RA including RA score and serum levels of IL-6, CRP, ESR, DAS28-CRP, DAS28-ESR, Swollen joints and Tender joints. Bisulfite sequencing (BSP-seq) was used to determine the DNA methylation in Smad7 promoter (-1000 to +2000) region in CD4+ T cells. In addition, a DNA methylation inhibitor, 5-Azacytidine (5-AzaC), was added to CD4+ T cells to examine the possible role of Smad7 methylation in CD4+ T cell differentiation and functional activity.ResultsCompared to the heath controls, Smad7 expression was significantly decreased in CD4+ T cells from RA patients and inversely co...

The long noncoding RNA Meg3 mediates TLR4-induced inflammation in experimental obstructive nephropathy

Clinical Science

Kidney inflammation contributes to the progression of chronic kidney disease (CKD). Modulation of... more Kidney inflammation contributes to the progression of chronic kidney disease (CKD). Modulation of Toll-like receptor 4 (TLR4) signaling is a potential therapeutic strategy for this pathology, but the regulatory mechanisms of TLR4 signaling in kidney tubular inflammation remains unclear. Here, we demonstrated that tubule-specific deletion of TLR4 in mice conferred protection against obstruction-induced kidney injury, with reduction in inflammatory cytokine production, macrophage infiltration and kidney fibrosis. Transcriptome analysis revealed a marked down-regulation of long noncoding RNA (lncRNA) Meg3 in the obstructed kidney from tubule-specific TLR4 knockout mice compared with wild-type control. Meg3 was also induced by lipopolysaccharide in tubular epithelial cells via a p53-dependent signaling pathway. Silencing of Meg3 suppressed LPS-induced cytokine production of CCL-2 and CXCL-2 and the activation of p38 MAPK pathway in vitro and ameliorated kidney fibrosis in mice with obst...

Signaling mechanisms of SARS-CoV-2 Nucleocapsid protein in viral infection, cell death and inflammation

International Journal of Biological Sciences

COVID-19 which is caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) has posed ... more COVID-19 which is caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) has posed a worldwide pandemic and a major global public health threat. SARS-CoV-2 Nucleocapsid (N) protein plays a critical role in multiple steps of the viral life cycle and participates in viral replication, transcription, and assembly. The primary roles of N protein are to assemble with genomic RNA into the viral RNAprotein (vRNP) complex and to localize to the replication transcription complexes (RTCs) to enhance viral replication and transcription. N protein can also undergo liquid-liquid phase separation (LLPS) with viral genome RNA and inhibit stress granules to facilitate viral replication and assembly. Besides the function in viral life cycle, N protein can bind GSDMD to antagonize pyroptosis but promotes cell death via the Smad3-dependent G1 cell cycle arrest mechanism. In innate immune system, N protein inhibits IFN-β production and RNAi pathway for virus survival. However, it can induce expression of proinflammatory cytokines by activating NF-κB signaling and NLRP3 inflammasome, resulting in cytokine storms. In this review article, we are focusing on the signaling mechanisms of SARS-CoV-2 N protein in viral replication, cell death and inflammation.

Single-Cell RNA Sequencing Reveals the Immunological Profiles of Renal Allograft Rejection in Mice

Frontiers in Immunology, 2021

Allograft rejection is a common immunological feature in renal transplantation and is associated ... more Allograft rejection is a common immunological feature in renal transplantation and is associated with reduced graft survival. A mouse renal allograft rejection model was induced and single-cell RNA sequencing (scRNA-seq) data of CD45+leukocytes in kidney allografts on days 7 (D7) and 15 (D15) after operation was analyzed to reveal a full immunological profiling. We identified 20 immune cell types among 10,921 leukocytes. Macrophages and CD8+T cells constituted the main populations on both timepoints. In the process from acute rejection (AR) towards chronic rejection (CR), the proportion of proliferating and naïve CD8+T cells dropped significantly. Both B cells and neutrophils decreased by about 3 folds. On the contrary, the proportion of macrophages and dendritic cells (DCs) increased significantly, especially by about a 4.5-fold increase in Ly6cloMrc1+macrophages and 2.6 folds increase in Ly6cloEar2+macrophages. Moreover, myeloid cells harbored the richest ligand and receptor (LR) ...

Challenges and Recent Advances in NK Cell-Targeted Immunotherapies in Solid Tumors

International Journal of Molecular Sciences, 2021

Natural killer (NK) cell is a powerful malignant cells killer, providing rapid immune responses v... more Natural killer (NK) cell is a powerful malignant cells killer, providing rapid immune responses via direct cytotoxicity without the need of antigen processing and presentation. It plays an essential role in preventing early tumor, metastasis and minimal residual disease. Although adoptive NK therapies achieved great success in clinical trials against hematologic malignancies, their accumulation, activation, cytotoxic and immunoregulatory functions are severely impaired in the immunosuppressive microenvironment of solid tumors. Now with better understandings of the tumor evasive mechanisms from NK-mediated immunosurveillance, immunotherapies targeting the key molecules for NK cell dysfunction and exhaustion have been developed and tested in both preclinical and clinical studies. In this review, we introduce the challenges that NK cells encountered in solid tumor microenvironment (TME) and the therapeutic approaches to overcome these limitations, followed by an outline of the recent p...

Deoxyspergualin inhibits mesangial cell proliferation and major histocompatibility complex class II expression

Journal of the American Society of Nephrology, 1995

It has previously been shown that the immunosuppressive drug deoxyspergualin can inhibit renal in... more It has previously been shown that the immunosuppressive drug deoxyspergualin can inhibit renal injury in experimental glomerulonephritis. This study examined whether deoxyspergualin can modulate the mesangial cell response to glomerular injury. Antiglomerular basement membrane glomerulonephritis was induced in primed rats. Groups of five animals were treated with deoxyspergualin (5 mg/kg per day) or saline from Day 0 until being euthanized on Day 1, 7, 14, or 21. Deoxyspergualin treatment significantly inhibited mesangial cell proliferation (proliferating cell nuclear antigen expression) over the disease course as assessed by double immunohistochemistry staining (P < 0.001 versus saline treated) and reduced glomerular major histocompatibility complex (MHC) class II expression. To demonstrate if this was a direct action of deoxyspergualin, an in vitro system was studied. The addition of deoxyspergualin caused a time- and dose-dependent inhibition of [3H]thymidine uptake by culture...

MIF Expression in the Rat Brain: Implications for Neuronal Function

Molecular Medicine, 1998

Background: The mediator known historically as macrophage migration inhibitory factor (MIF) has b... more Background: The mediator known historically as macrophage migration inhibitory factor (MIF) has been identified recently as being released into the circulation by the anterior pituitary gland as a consequence of stress or during a systemic inflamnnatory response. Macrophages and T cells also secrete MIF, both in response to proin-IL-1,B, and IL-6. Conclusion: The significant levels of baseline and inducible MIF expression in the brain and its regional association with glucocorticoid action underscore the importance of this mediator as a physiological regulator of the inflammatory stress response and further define its role within the neuroendocrine system.

Long Non-coding RNA_5318 is a Novel Therapeutic Target for Renal Fibrosis in Obstructive Nephropathy

Hong Kong Journal of Nephrology, 2015

Background: Higher glomerular PLA2R-antigen deposit (GAg) rates compared with serum phospholipase... more Background: Higher glomerular PLA2R-antigen deposit (GAg) rates compared with serum phospholipase A2 receptor-antibody (SAb) positive rates were reported. However, the exact roles played by these two biomarkers remain unknown. Methods: A total of 572 patients diagnosed with IMN were included. Both SAb and GAg were detected. Fifty-two IMN patients received repeat renal biopsy were included. Results: 572 patients, 401 (70.1%) were SAb positive (SAb+) while 171 (29.9%) were SAb negative (SAb-). In SAb+ patients, the glomerular PLA2R-antigen deposition (GAg+) was observed in 99.1% (397/401). Interestingly, the GAg+ was observed in 68.4% (117/171) Sab patients. Patients with SAb manifested more severe proteinuria (3.9 g/24 hours vs. 2.8 g/24 hours, P < 0.001) and lower eGFR (104 ml/min/1.73 m 2 vs. 110 ml/min/1.73 m 2 , P Z 0.002) than patients without SAb. Further comparison between SAb+/GAg+ and SAb-/GAg+ showed a similar profile. Patients with SAb+/GAg+ also showed lower chance of proteinuria remission and higher chance of renal function decline in the follow up when compared to patients with SAb-/GAg+. Changes of SAb and GAg were observed in patients with repeat renal biopsy, in 11 patients the SAb+ turned into SAb-, among them 1 patient failed to achieve remission, 7 patients achieved remission and 4 remitted during the interval but relapsed at the time of repeat biopsy. While the GAg+ turned into GAg-in only 3 patients, all achieved remission at the repeat biopsy. The proportion of GAg disappearance was lower than SAb (P Z 0.016). Conclusion: The GAg deposit can be detected in a large proportion of SAb negative patients, which can be explained by the lag of GAg disappearance in the follow up. SAb was more tightly correlated to disease activity, treatment response and prognosis than GAg. We recommend adopting GAg deposit detection as a supplement to SAb in IMN diagnosis and continuing to monitor SAb during follow-up.

C-Reactive Protein Exacerbates Diabetic Kidney Fibrosis by Enhancing CD32-Smad3-mTOR Signaling in Human CRP-Tg/db/db Mice

Hong Kong Journal of Nephrology, 2015

Objectives: AMP-activated protein kinase (AMPK), which regulates wholebody energy metabolism and ... more Objectives: AMP-activated protein kinase (AMPK), which regulates wholebody energy metabolism and has emerged an attractive target metabolism syndrome, especially on lipid metabolic disorder in type 2 diabetes. To evaluate the role of Tangshen Formular (TSF) in regulating liver dyslipidemia in diabetes, db/db mice were randomized to a standard diet (SD) or SD plus TSF for 12 weeks and db/m mice as a control. Methods and results: we demonstrated that TSF significant suppressed mice weight gain and liver steatosis with lipid accumulation (Oil Red O &HE staining results). These changes were accompanied by modulation of insulin and AMPK/SREBP signaling. The administration of TSF increased the phosphorylation of AMPK and decreased SREBP-1 nuclear translocation. Moreover, the target genes of SREBP-1 such as FAS, ACC, and SCD1, at both mRNA and protein levels were also decreased in mouse received TSF. TSF also potently inhibited de novo lipogenesis and stimulated fatty acid combustion in mice liver with downregulation of hepatic gluconeogenesis/lipogenesis genes (PGC-1a, Acadm, Acox1). Conclusion: TSF may be a potential promising theraputic approach to attenuate fatty liver, dyslipidemia and obesity-related diseases.

Circulating microRNAs as markers for prediction of heart failure medical treatment outcome

European Heart Journal, 2013

Purpose: Chronic heart failure (HF) is a major worldwide health care problem. Despite significant... more Purpose: Chronic heart failure (HF) is a major worldwide health care problem. Despite significant improvement of mortality and morbidity with medical therapy, not all patients respond well to the treatment. This "lack of response" has not been adequately explored and currently no biomarker is available to indicate which patient will respond medical treatment non-responders. As circulating microRNAs have been described as potential biomarkers in various heart diseases, we explored the role circulating microRNAs as potential biomarkers of HF and as predictors of treatment outcome. Methods: MicroRNA arrays were performed from plasma of 9 healthy controls, 10 HF treatment Non-responders, and 10 HF treatment Responders at 6-month follow up. HF treatment "Non-responders" was defined as death, re-hospitalization for HF, and/or reduction of left ventricular end-systolic volume of <10% in 6 months despite standard HF medication therapy. Then we selected 15 microR-NAs with significant changes for further validation by quantitative real-time PCR assays with the plasma samples from another 17 healthy controls, 13 Nonresponders and 13 Responders at 6-month follow up. Finally, we determined the diagnostic accuracy of these candidate microRNAs. Results: Our results showed that 3 of 5 microRNAs previously reported in HF patients (miR-423-5p,-320a,-17,-92a, and-22) failed to predict the treatment outcome. We identified 7 fibrosis-and inflammation-related microRNAs (including miR-27b,-221,-222,-140-3p,-155,-29b, and-31) were altered in HF patients. More importantly, they were able to predict the HF patients as receiver operator characteristics (ROC) curve analysis demonstrated higher predictive power of these 7 microRNAs within the HF registry, when comparing to healthy controls (AUC >0.87, P<0.01). After 6-month treatment, the plasma levels of these 7 mi-croRNAs were altered in the Responders (P<0.05) as their levels did not show any significant changes in Non-responders. Analyses from comparison of ROC (AUC>0.90 for Responder and AUC<0.55 for Responder at 6-month follow up, P<0.05) and the Wilcoxon matched pairs test (P<0.05) confirmed the ability of these 7 microRNAs to discriminate the treatment Non-responders and Responders [PCY1] Conclusion: We identified 7 microRNAs (miR-27b,-221,-222,-29b,-31,-140-3p, and-155) as the effective biomarkers for HF and they possess a high discriminatory ability to distinguish HF treatment Non-responders from Responders. Our studies suggest that these 7 microRNAs are putative effective biomarkers of HF and of predicting treatment Non-responders. P4215 | BEDSIDE Differentiation of left ventricular systolic dysfunction related to cardiac sarcoidosis and other heart diseases using contrast-enhanced cardiovascular magnetic resonance

Role of interleukin-1 in mesangial cell proliferation and matrix deposition in experimental mesangioproliferative nephritis

The American journal of pathology, 1997

We examined the functional role of interleukin (IL)-1 in mesangial cell proliferation during rat ... more We examined the functional role of interleukin (IL)-1 in mesangial cell proliferation during rat anti-Thy-1 nephritis by blocking its action with IL-1 receptor antagonist (IL-1ra). Anti-Thy-1 nephritis was induced by intravenous injection of 5 mg/kg OX-7 IgG (day 0) into inbred Wistar rats. Groups of animals (n = 9) were implanted with a micro-osmotic pump on day -1, which delivered 25 micrograms/hour human recombinant IL-1ra or saline continuously until the rats were killed at day 6, the peak of mesangial cell proliferation. Immunostaining showed that IL-1 was expressed by mesangial cells during disease. IL-1ra treatment did not affect the mild, but significant, proteinuria seen after OX-7 injection. Compared with saline treatment, IL-1ra treatment reduced mesangial cell proliferation (decreases 24% P < 0.05), glomerular hypercellularity (decreases 29%; P < 0.05), and glomerular macrophage accumulation (decreases 20%; P < 0.05). However, IL-1ra treatment had no effect on g...

Migration inhibitory factor expression in experimentally induced endotoxemia

The American journal of pathology, 1997

Macrophage migration inhibitory factor (MIF) is an important constituent of the host response to ... more Macrophage migration inhibitory factor (MIF) is an important constituent of the host response to stress and infection and is the first mediator that has been identified to be released from immune cells upon stimulation with glucocorticoids. MIF also has been shown to be secreted from the anterior pituitary gland, monocytes/macrophages, and T cells activated by various proinflammatory stimuli. Once released, MIF acts to counter-regulate the inhibitory effect of glucocorticoids on inflammatory cytokine production. To characterize more precisely the role of MIF in the host response to infection, we undertook a systematic analysis of MIF expression in various organs of the rat after endotoxin (lipopolysaccharide) administration. MIF protein and mRNA were analyzed by immunohistochemistry and in situ hybridization, respectively. MIF was found to be expressed constitutively in organs such as the lung, liver, kidney, spleen, adrenal gland, and skin. Significant quantities of MIF protein wer...

Genome-wide network model capturing seed germination reveals coordinated regulation of plant cellular phase transitions

Proceedings of the National Academy of Sciences, 2011

Seed germination is a complex trait of key ecological and agronomic significance. Few genetic fac... more Seed germination is a complex trait of key ecological and agronomic significance. Few genetic factors regulating germination have been identified, and the means by which their concerted action controls this developmental process remains largely unknown. Using publicly available gene expression data from Arabidopsis thaliana , we generated a condition-dependent network model of global transcriptional interactions (SeedNet) that shows evidence of evolutionary conservation in flowering plants. The topology of the SeedNet graph reflects the biological process, including two state-dependent sets of interactions associated with dormancy or germination. SeedNet highlights interactions between known regulators of this process and predicts the germination-associated function of uncharacterized hub nodes connected to them with 50% accuracy. An intermediate transition region between the dormancy and germination subdomains is enriched with genes involved in cellular phase transitions. The phase...

Interleukin‐10 differentially modulates MHC class II expression by mesangial cells and macrophages in vitro and in vivo

Immunology, 2001

Inhibition of major histocompatibility complex (MHC) class II expression by macrophages is the pr... more Inhibition of major histocompatibility complex (MHC) class II expression by macrophages is the primary mechanism by which interleukin‐10 (IL‐10) exerts imm_une suppression. Little, however, is known of the effects of IL‐10 on other types of cells which can be induced to express MHC class II during an inflammatory response. We therefore studied the effects of IL‐10 treatment on the expression of MHC class II molecules in a rat model of imm_unologically induced glomerulonephritis. MHC class II mRNA levels in whole kidney were increased in saline‐treated (control) animals with glomerulonephritis (2·6‐fold increase versus normal, P=0·028) and this was partially inhibited by treatment with IL‐10 (P=NS). Double imm_unostaining of tissue sections was used to compare MHC class II expression by infiltrating macrophages and resident glomerular cells. IL‐10 treatment reduced the proportion of glomerular macrophages which expressed detectable MHC class II (70% reduction, P=0·03). In contrast, I...

Suppression of pulmonary injury in experimental ‘Goodpasture's syndrome’ by deoxyspergualin (DSP)

Clinical and Experimental Immunology, 2008

SUMMARY DSP is a potent immunosuppressive drug which can prevcnt allograft rejection and suppress... more SUMMARY DSP is a potent immunosuppressive drug which can prevcnt allograft rejection and suppress acute rejection episodes. In this study, the ability of DSP to suppress pulmonary injury in experimental Goodpasture's syndrome was investigated. Passive accelerated anti-glomerular basement membrane (GBM) disease was induced in rats by priming with rabbit IgG. followed 5 days later by injection of rabbit anti-GBM serum (day 0). Groups of five animals were treated with DSP (5 mg/kg iniraperitoneally per day) or saline (untreated) from day 0 until being killed on days 1,7,14or21. At day I, both DSP-treated and untreated animals exhibited similar pulmonary haemorrhage, oedema, and prominent perivascular leucocyte infiltration. Untreated animals subsequently developed severe widespread pulmonary damage including granulomatous lesions and extensive fibrosis, which correlated with infiltration of macrophages and immune-activated (IL-2R′) mononuelcar cells (P<0·01). Tumour necrosis fac...

Macrophage apoptosis in rat crescentic glomerulonephritis

Up-regulation of macrophage migration-inhibitory factor expression after compression-induced spinal cord injury in rats

Acta Neuropathologica, 2004

Macrophage migration inhibitory factor (MIF) is a multipotential protein that acts as a pro-infla... more Macrophage migration inhibitory factor (MIF) is a multipotential protein that acts as a pro-inflammatory cytokine, pituitary hormone, immunoregulator, and mitogen. To elucidate function of MIF in spinal cord injury, we examined expression of MIF after compression-induced spinal cord injury using Northern blot analysis, in situ hybridization and immunohistochemistry. The MIF mRNA was up-regulated in injured spinal cord, peaking 3 days after injury shown by Northern blot analysis. In situ hybridization revealed up-regulation of MIF in microglia accumulating in the lesion epicenter 3 days after injury and astrocytes around the cystic cavity 1 week after injury. Double staining showed co-localization of MIF and tomato lectin in the lesioned site, indicating that microglia accumulating to the lesion epicenter express MIF. The time course of MIF expression is different from that of previous reports about cytokine expression peaking at earlier time points; thus, it is unlikely that MIF acts as a pro-inflammatory factor in the present study. The MIF may contribute to proliferation of astrocytes around the lesioned site in spinal cord injury because of its cell proliferation-promoting property.

AANG Prevents Smad3-dependent Diabetic Nephropathy by Restoring Pancreatic β-Cell Development in db/db Mice

International Journal of Biological Sciences

Diabetic nephropathy (DN) is a major cause of end-stage kidney disease, where TGF-β1/Smad signali... more Diabetic nephropathy (DN) is a major cause of end-stage kidney disease, where TGF-β1/Smad signaling plays an important role in the disease progression. Our previous studies demonstrated a combination of Traditional Chinese Medicine derived Smad7 agonist Asiatic Acid (AA) and Smad3 inhibitor Naringenin (NG), AANG, effectively suppressed the progression of renal fibrosis in vivo. However, its implication in type-2 diabetic nephropathy (T2DN) is still unexplored. Here, we detected progressive activation of Smad3 but reduction of Smad7 in db/db mice during T2DN development. Therefore, we optimized the dosage and the combination ratio of AANG to achieve a better rebalancing Smad3/Smad7 signaling for treatment of T2DN. Unexpectedly, preventive treatment with combined AANG from week 4 before the development of diabetes and T2DN effectively protected against the onset of T2DN. In contract, these inhibitory effects were lost when db/db mice received the late AANG treatment from 12-24 weeks. Surprisingly, preventive treatment with AANG ameliorated not only T2DN but also the primary disease type-2 diabetes (T2D) with relative normal levels of fasting blood glucose and HbA1c, and largely improving metabolic abnormalities especially on insulin insensitivity and glucose tolerance in db/db mice. Mechanistically, AANG effectively prevented both Smad3-mediated renal fibrosis and NF-κB-driven renal inflammation in the diabetic kidney in vivo and advanced glycation end-products (AGE) stimulated tubular epithelial mTEC cells in vitro. More importantly, we uncovered that preventive treatment with AANG effectively protected against diabetic-associated islet injury via restoring the β cell development in db/db mice. Taken together, we discovered that the early treatment with combined AANG can effectively protect against the development of T2D and T2DN via mechanism associated with protection against Smad3-depenedent islet injury.

Novel lncRNA Erbb4-IR Promotes Diabetic Kidney Injury in db/db Mice by Targeting miR-29b

Diabetes, Apr 8, 2017

TGF-β/Smad signaling plays an important role in diabetic nephropathy. The present study identifie... more TGF-β/Smad signaling plays an important role in diabetic nephropathy. The present study identified a novel Smad3-dependent long non-coding RNA (lncRNA) Erbb4-IR in the development of type-2 diabetic nephropathy (T2DN) in db/db mice. We found that Erbb4-IR was highly expressed in T2DN of db/db mice and was specifically induced by AGE via a Smad3-dependent mechanism. The functional role of Erbb4-IR in T2DN was revealed by kidney-specific silencing of Erbb4-IR to protect against the development of T2DN such as elevated microalbuminuria, serum creatinine and progressive renal fibrosis in db/db mice, and to block AGE-induced collagen I and IV expression in mouse mesangial cells (mMCs) and mouse tubular epithelial cells (mTECs). Mechanistically, we identified that the Erbb4-IR-miR-29b axis was a key mechanism of T2DN because Erbb4-IR was able to bind the 3'UTR of miR-29b genomic sequence to suppress miR-29b expression at transcriptional level. In contrast, silencing of renal Erbb4-IR ...

CXCL9, but not CXCL10, Promotes CXCR3-Dependent Immune-Mediated Kidney Disease

Journal of the American Society of Nephrology, 2008

Chemokines are instrumental in macrophage-and T cell-dependent diseases. The chemokine CCL2 promo... more Chemokines are instrumental in macrophage-and T cell-dependent diseases. The chemokine CCL2 promotes kidney disease in two models of immune-mediated nephritis (MRL-Fas lpr mice and the nephrotoxic serum nephritis model), but evidence suggests that multiple chemokines are involved. For identification of additional therapeutic targets for immune-mediated nephritis, chemokine ligands and receptors in CCL2 Ϫ/Ϫ and wild-type (WT) MRL-Fas lpr kidneys were profiled. The focus was on intrarenal chemokine ligand/receptor pairs that were highly upregulated downstream of CCL2; the chemokine CXCL10 and its cognate receptor, CXCR3, stood out as potential therapeutic targets. However, renal disease was not suppressed in CXCL10 Ϫ/Ϫ MRL-Fas lpr mice, and CXCL10 Ϫ/Ϫ C57BL/6 mice were not protected from nephrotoxic serum nephritis compared with WT mice. Because CXCR3 engages with the ligand CXCL9, CXCR3 Ϫ/Ϫ , CXCL9 Ϫ/Ϫ , and CXCL10 Ϫ/Ϫ B6 mice were compared with WT mice with nephrotoxic serum nephritis. Kidney disease, measured by loss of renal function and histopathology, was suppressed in both CXCR3 Ϫ/Ϫ and CXCL9 Ϫ/Ϫ mice but not in CXCL10 Ϫ/Ϫ mice. With nephrotoxic serum nephritis, CXCR3 Ϫ/Ϫ and CXCL9 Ϫ/Ϫ mice had fewer intrarenal activated T cells and activated macrophages. Both IgG glomerular deposits and antigen-specific IgG in serum were reduced in these mice, suggesting that although CXCR3 and CXCL9 initiate nephritis through cell-mediated events, renal inflammation may be sustained by their regulation of IgG. It is concluded that specific blockade of CXCL9 or CXCR3 may be a potential therapeutic target for human immune-mediated kidney diseases.

Hypermethylation of Smad7 in CD4+ T cells is associated with the disease activity of rheumatoid arthritis

Frontiers in Immunology

BackgroundSmad7 is protective in a mouse model of rheumatoid arthritis. Here we investigated whet... more BackgroundSmad7 is protective in a mouse model of rheumatoid arthritis. Here we investigated whether Smad7-expressing CD4+ T cells and the methylation of Smad7 gene in CD4+ T cells contribute to the disease activity of RA in patients.MethodsPeripheral CD4+ T cells were collected from 35 healthy controls and 57 RA patients. Smad7 expression by CD4+ T cells were determined and correlated with the clinical parameters of RA including RA score and serum levels of IL-6, CRP, ESR, DAS28-CRP, DAS28-ESR, Swollen joints and Tender joints. Bisulfite sequencing (BSP-seq) was used to determine the DNA methylation in Smad7 promoter (-1000 to +2000) region in CD4+ T cells. In addition, a DNA methylation inhibitor, 5-Azacytidine (5-AzaC), was added to CD4+ T cells to examine the possible role of Smad7 methylation in CD4+ T cell differentiation and functional activity.ResultsCompared to the heath controls, Smad7 expression was significantly decreased in CD4+ T cells from RA patients and inversely co...

The long noncoding RNA Meg3 mediates TLR4-induced inflammation in experimental obstructive nephropathy

Clinical Science

Kidney inflammation contributes to the progression of chronic kidney disease (CKD). Modulation of... more Kidney inflammation contributes to the progression of chronic kidney disease (CKD). Modulation of Toll-like receptor 4 (TLR4) signaling is a potential therapeutic strategy for this pathology, but the regulatory mechanisms of TLR4 signaling in kidney tubular inflammation remains unclear. Here, we demonstrated that tubule-specific deletion of TLR4 in mice conferred protection against obstruction-induced kidney injury, with reduction in inflammatory cytokine production, macrophage infiltration and kidney fibrosis. Transcriptome analysis revealed a marked down-regulation of long noncoding RNA (lncRNA) Meg3 in the obstructed kidney from tubule-specific TLR4 knockout mice compared with wild-type control. Meg3 was also induced by lipopolysaccharide in tubular epithelial cells via a p53-dependent signaling pathway. Silencing of Meg3 suppressed LPS-induced cytokine production of CCL-2 and CXCL-2 and the activation of p38 MAPK pathway in vitro and ameliorated kidney fibrosis in mice with obst...

Signaling mechanisms of SARS-CoV-2 Nucleocapsid protein in viral infection, cell death and inflammation

International Journal of Biological Sciences

COVID-19 which is caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) has posed ... more COVID-19 which is caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) has posed a worldwide pandemic and a major global public health threat. SARS-CoV-2 Nucleocapsid (N) protein plays a critical role in multiple steps of the viral life cycle and participates in viral replication, transcription, and assembly. The primary roles of N protein are to assemble with genomic RNA into the viral RNAprotein (vRNP) complex and to localize to the replication transcription complexes (RTCs) to enhance viral replication and transcription. N protein can also undergo liquid-liquid phase separation (LLPS) with viral genome RNA and inhibit stress granules to facilitate viral replication and assembly. Besides the function in viral life cycle, N protein can bind GSDMD to antagonize pyroptosis but promotes cell death via the Smad3-dependent G1 cell cycle arrest mechanism. In innate immune system, N protein inhibits IFN-β production and RNAi pathway for virus survival. However, it can induce expression of proinflammatory cytokines by activating NF-κB signaling and NLRP3 inflammasome, resulting in cytokine storms. In this review article, we are focusing on the signaling mechanisms of SARS-CoV-2 N protein in viral replication, cell death and inflammation.

Single-Cell RNA Sequencing Reveals the Immunological Profiles of Renal Allograft Rejection in Mice

Frontiers in Immunology, 2021

Allograft rejection is a common immunological feature in renal transplantation and is associated ... more Allograft rejection is a common immunological feature in renal transplantation and is associated with reduced graft survival. A mouse renal allograft rejection model was induced and single-cell RNA sequencing (scRNA-seq) data of CD45+leukocytes in kidney allografts on days 7 (D7) and 15 (D15) after operation was analyzed to reveal a full immunological profiling. We identified 20 immune cell types among 10,921 leukocytes. Macrophages and CD8+T cells constituted the main populations on both timepoints. In the process from acute rejection (AR) towards chronic rejection (CR), the proportion of proliferating and naïve CD8+T cells dropped significantly. Both B cells and neutrophils decreased by about 3 folds. On the contrary, the proportion of macrophages and dendritic cells (DCs) increased significantly, especially by about a 4.5-fold increase in Ly6cloMrc1+macrophages and 2.6 folds increase in Ly6cloEar2+macrophages. Moreover, myeloid cells harbored the richest ligand and receptor (LR) ...

Challenges and Recent Advances in NK Cell-Targeted Immunotherapies in Solid Tumors

International Journal of Molecular Sciences, 2021

Natural killer (NK) cell is a powerful malignant cells killer, providing rapid immune responses v... more Natural killer (NK) cell is a powerful malignant cells killer, providing rapid immune responses via direct cytotoxicity without the need of antigen processing and presentation. It plays an essential role in preventing early tumor, metastasis and minimal residual disease. Although adoptive NK therapies achieved great success in clinical trials against hematologic malignancies, their accumulation, activation, cytotoxic and immunoregulatory functions are severely impaired in the immunosuppressive microenvironment of solid tumors. Now with better understandings of the tumor evasive mechanisms from NK-mediated immunosurveillance, immunotherapies targeting the key molecules for NK cell dysfunction and exhaustion have been developed and tested in both preclinical and clinical studies. In this review, we introduce the challenges that NK cells encountered in solid tumor microenvironment (TME) and the therapeutic approaches to overcome these limitations, followed by an outline of the recent p...

Deoxyspergualin inhibits mesangial cell proliferation and major histocompatibility complex class II expression

Journal of the American Society of Nephrology, 1995

It has previously been shown that the immunosuppressive drug deoxyspergualin can inhibit renal in... more It has previously been shown that the immunosuppressive drug deoxyspergualin can inhibit renal injury in experimental glomerulonephritis. This study examined whether deoxyspergualin can modulate the mesangial cell response to glomerular injury. Antiglomerular basement membrane glomerulonephritis was induced in primed rats. Groups of five animals were treated with deoxyspergualin (5 mg/kg per day) or saline from Day 0 until being euthanized on Day 1, 7, 14, or 21. Deoxyspergualin treatment significantly inhibited mesangial cell proliferation (proliferating cell nuclear antigen expression) over the disease course as assessed by double immunohistochemistry staining (P < 0.001 versus saline treated) and reduced glomerular major histocompatibility complex (MHC) class II expression. To demonstrate if this was a direct action of deoxyspergualin, an in vitro system was studied. The addition of deoxyspergualin caused a time- and dose-dependent inhibition of [3H]thymidine uptake by culture...

MIF Expression in the Rat Brain: Implications for Neuronal Function

Molecular Medicine, 1998

Background: The mediator known historically as macrophage migration inhibitory factor (MIF) has b... more Background: The mediator known historically as macrophage migration inhibitory factor (MIF) has been identified recently as being released into the circulation by the anterior pituitary gland as a consequence of stress or during a systemic inflamnnatory response. Macrophages and T cells also secrete MIF, both in response to proin-IL-1,B, and IL-6. Conclusion: The significant levels of baseline and inducible MIF expression in the brain and its regional association with glucocorticoid action underscore the importance of this mediator as a physiological regulator of the inflammatory stress response and further define its role within the neuroendocrine system.

Long Non-coding RNA_5318 is a Novel Therapeutic Target for Renal Fibrosis in Obstructive Nephropathy

Hong Kong Journal of Nephrology, 2015

Background: Higher glomerular PLA2R-antigen deposit (GAg) rates compared with serum phospholipase... more Background: Higher glomerular PLA2R-antigen deposit (GAg) rates compared with serum phospholipase A2 receptor-antibody (SAb) positive rates were reported. However, the exact roles played by these two biomarkers remain unknown. Methods: A total of 572 patients diagnosed with IMN were included. Both SAb and GAg were detected. Fifty-two IMN patients received repeat renal biopsy were included. Results: 572 patients, 401 (70.1%) were SAb positive (SAb+) while 171 (29.9%) were SAb negative (SAb-). In SAb+ patients, the glomerular PLA2R-antigen deposition (GAg+) was observed in 99.1% (397/401). Interestingly, the GAg+ was observed in 68.4% (117/171) Sab patients. Patients with SAb manifested more severe proteinuria (3.9 g/24 hours vs. 2.8 g/24 hours, P < 0.001) and lower eGFR (104 ml/min/1.73 m 2 vs. 110 ml/min/1.73 m 2 , P Z 0.002) than patients without SAb. Further comparison between SAb+/GAg+ and SAb-/GAg+ showed a similar profile. Patients with SAb+/GAg+ also showed lower chance of proteinuria remission and higher chance of renal function decline in the follow up when compared to patients with SAb-/GAg+. Changes of SAb and GAg were observed in patients with repeat renal biopsy, in 11 patients the SAb+ turned into SAb-, among them 1 patient failed to achieve remission, 7 patients achieved remission and 4 remitted during the interval but relapsed at the time of repeat biopsy. While the GAg+ turned into GAg-in only 3 patients, all achieved remission at the repeat biopsy. The proportion of GAg disappearance was lower than SAb (P Z 0.016). Conclusion: The GAg deposit can be detected in a large proportion of SAb negative patients, which can be explained by the lag of GAg disappearance in the follow up. SAb was more tightly correlated to disease activity, treatment response and prognosis than GAg. We recommend adopting GAg deposit detection as a supplement to SAb in IMN diagnosis and continuing to monitor SAb during follow-up.

C-Reactive Protein Exacerbates Diabetic Kidney Fibrosis by Enhancing CD32-Smad3-mTOR Signaling in Human CRP-Tg/db/db Mice

Hong Kong Journal of Nephrology, 2015

Objectives: AMP-activated protein kinase (AMPK), which regulates wholebody energy metabolism and ... more Objectives: AMP-activated protein kinase (AMPK), which regulates wholebody energy metabolism and has emerged an attractive target metabolism syndrome, especially on lipid metabolic disorder in type 2 diabetes. To evaluate the role of Tangshen Formular (TSF) in regulating liver dyslipidemia in diabetes, db/db mice were randomized to a standard diet (SD) or SD plus TSF for 12 weeks and db/m mice as a control. Methods and results: we demonstrated that TSF significant suppressed mice weight gain and liver steatosis with lipid accumulation (Oil Red O &HE staining results). These changes were accompanied by modulation of insulin and AMPK/SREBP signaling. The administration of TSF increased the phosphorylation of AMPK and decreased SREBP-1 nuclear translocation. Moreover, the target genes of SREBP-1 such as FAS, ACC, and SCD1, at both mRNA and protein levels were also decreased in mouse received TSF. TSF also potently inhibited de novo lipogenesis and stimulated fatty acid combustion in mice liver with downregulation of hepatic gluconeogenesis/lipogenesis genes (PGC-1a, Acadm, Acox1). Conclusion: TSF may be a potential promising theraputic approach to attenuate fatty liver, dyslipidemia and obesity-related diseases.

Circulating microRNAs as markers for prediction of heart failure medical treatment outcome

European Heart Journal, 2013

Purpose: Chronic heart failure (HF) is a major worldwide health care problem. Despite significant... more Purpose: Chronic heart failure (HF) is a major worldwide health care problem. Despite significant improvement of mortality and morbidity with medical therapy, not all patients respond well to the treatment. This "lack of response" has not been adequately explored and currently no biomarker is available to indicate which patient will respond medical treatment non-responders. As circulating microRNAs have been described as potential biomarkers in various heart diseases, we explored the role circulating microRNAs as potential biomarkers of HF and as predictors of treatment outcome. Methods: MicroRNA arrays were performed from plasma of 9 healthy controls, 10 HF treatment Non-responders, and 10 HF treatment Responders at 6-month follow up. HF treatment "Non-responders" was defined as death, re-hospitalization for HF, and/or reduction of left ventricular end-systolic volume of <10% in 6 months despite standard HF medication therapy. Then we selected 15 microR-NAs with significant changes for further validation by quantitative real-time PCR assays with the plasma samples from another 17 healthy controls, 13 Nonresponders and 13 Responders at 6-month follow up. Finally, we determined the diagnostic accuracy of these candidate microRNAs. Results: Our results showed that 3 of 5 microRNAs previously reported in HF patients (miR-423-5p,-320a,-17,-92a, and-22) failed to predict the treatment outcome. We identified 7 fibrosis-and inflammation-related microRNAs (including miR-27b,-221,-222,-140-3p,-155,-29b, and-31) were altered in HF patients. More importantly, they were able to predict the HF patients as receiver operator characteristics (ROC) curve analysis demonstrated higher predictive power of these 7 microRNAs within the HF registry, when comparing to healthy controls (AUC >0.87, P<0.01). After 6-month treatment, the plasma levels of these 7 mi-croRNAs were altered in the Responders (P<0.05) as their levels did not show any significant changes in Non-responders. Analyses from comparison of ROC (AUC>0.90 for Responder and AUC<0.55 for Responder at 6-month follow up, P<0.05) and the Wilcoxon matched pairs test (P<0.05) confirmed the ability of these 7 microRNAs to discriminate the treatment Non-responders and Responders [PCY1] Conclusion: We identified 7 microRNAs (miR-27b,-221,-222,-29b,-31,-140-3p, and-155) as the effective biomarkers for HF and they possess a high discriminatory ability to distinguish HF treatment Non-responders from Responders. Our studies suggest that these 7 microRNAs are putative effective biomarkers of HF and of predicting treatment Non-responders. P4215 | BEDSIDE Differentiation of left ventricular systolic dysfunction related to cardiac sarcoidosis and other heart diseases using contrast-enhanced cardiovascular magnetic resonance

Role of interleukin-1 in mesangial cell proliferation and matrix deposition in experimental mesangioproliferative nephritis

The American journal of pathology, 1997

We examined the functional role of interleukin (IL)-1 in mesangial cell proliferation during rat ... more We examined the functional role of interleukin (IL)-1 in mesangial cell proliferation during rat anti-Thy-1 nephritis by blocking its action with IL-1 receptor antagonist (IL-1ra). Anti-Thy-1 nephritis was induced by intravenous injection of 5 mg/kg OX-7 IgG (day 0) into inbred Wistar rats. Groups of animals (n = 9) were implanted with a micro-osmotic pump on day -1, which delivered 25 micrograms/hour human recombinant IL-1ra or saline continuously until the rats were killed at day 6, the peak of mesangial cell proliferation. Immunostaining showed that IL-1 was expressed by mesangial cells during disease. IL-1ra treatment did not affect the mild, but significant, proteinuria seen after OX-7 injection. Compared with saline treatment, IL-1ra treatment reduced mesangial cell proliferation (decreases 24% P < 0.05), glomerular hypercellularity (decreases 29%; P < 0.05), and glomerular macrophage accumulation (decreases 20%; P < 0.05). However, IL-1ra treatment had no effect on g...

Migration inhibitory factor expression in experimentally induced endotoxemia

The American journal of pathology, 1997

Macrophage migration inhibitory factor (MIF) is an important constituent of the host response to ... more Macrophage migration inhibitory factor (MIF) is an important constituent of the host response to stress and infection and is the first mediator that has been identified to be released from immune cells upon stimulation with glucocorticoids. MIF also has been shown to be secreted from the anterior pituitary gland, monocytes/macrophages, and T cells activated by various proinflammatory stimuli. Once released, MIF acts to counter-regulate the inhibitory effect of glucocorticoids on inflammatory cytokine production. To characterize more precisely the role of MIF in the host response to infection, we undertook a systematic analysis of MIF expression in various organs of the rat after endotoxin (lipopolysaccharide) administration. MIF protein and mRNA were analyzed by immunohistochemistry and in situ hybridization, respectively. MIF was found to be expressed constitutively in organs such as the lung, liver, kidney, spleen, adrenal gland, and skin. Significant quantities of MIF protein wer...

Genome-wide network model capturing seed germination reveals coordinated regulation of plant cellular phase transitions

Proceedings of the National Academy of Sciences, 2011

Seed germination is a complex trait of key ecological and agronomic significance. Few genetic fac... more Seed germination is a complex trait of key ecological and agronomic significance. Few genetic factors regulating germination have been identified, and the means by which their concerted action controls this developmental process remains largely unknown. Using publicly available gene expression data from Arabidopsis thaliana , we generated a condition-dependent network model of global transcriptional interactions (SeedNet) that shows evidence of evolutionary conservation in flowering plants. The topology of the SeedNet graph reflects the biological process, including two state-dependent sets of interactions associated with dormancy or germination. SeedNet highlights interactions between known regulators of this process and predicts the germination-associated function of uncharacterized hub nodes connected to them with 50% accuracy. An intermediate transition region between the dormancy and germination subdomains is enriched with genes involved in cellular phase transitions. The phase...

Interleukin‐10 differentially modulates MHC class II expression by mesangial cells and macrophages in vitro and in vivo

Immunology, 2001

Inhibition of major histocompatibility complex (MHC) class II expression by macrophages is the pr... more Inhibition of major histocompatibility complex (MHC) class II expression by macrophages is the primary mechanism by which interleukin‐10 (IL‐10) exerts imm_une suppression. Little, however, is known of the effects of IL‐10 on other types of cells which can be induced to express MHC class II during an inflammatory response. We therefore studied the effects of IL‐10 treatment on the expression of MHC class II molecules in a rat model of imm_unologically induced glomerulonephritis. MHC class II mRNA levels in whole kidney were increased in saline‐treated (control) animals with glomerulonephritis (2·6‐fold increase versus normal, P=0·028) and this was partially inhibited by treatment with IL‐10 (P=NS). Double imm_unostaining of tissue sections was used to compare MHC class II expression by infiltrating macrophages and resident glomerular cells. IL‐10 treatment reduced the proportion of glomerular macrophages which expressed detectable MHC class II (70% reduction, P=0·03). In contrast, I...

Suppression of pulmonary injury in experimental ‘Goodpasture's syndrome’ by deoxyspergualin (DSP)

Clinical and Experimental Immunology, 2008

SUMMARY DSP is a potent immunosuppressive drug which can prevcnt allograft rejection and suppress... more SUMMARY DSP is a potent immunosuppressive drug which can prevcnt allograft rejection and suppress acute rejection episodes. In this study, the ability of DSP to suppress pulmonary injury in experimental Goodpasture's syndrome was investigated. Passive accelerated anti-glomerular basement membrane (GBM) disease was induced in rats by priming with rabbit IgG. followed 5 days later by injection of rabbit anti-GBM serum (day 0). Groups of five animals were treated with DSP (5 mg/kg iniraperitoneally per day) or saline (untreated) from day 0 until being killed on days 1,7,14or21. At day I, both DSP-treated and untreated animals exhibited similar pulmonary haemorrhage, oedema, and prominent perivascular leucocyte infiltration. Untreated animals subsequently developed severe widespread pulmonary damage including granulomatous lesions and extensive fibrosis, which correlated with infiltration of macrophages and immune-activated (IL-2R′) mononuelcar cells (P<0·01). Tumour necrosis fac...

Macrophage apoptosis in rat crescentic glomerulonephritis

Up-regulation of macrophage migration-inhibitory factor expression after compression-induced spinal cord injury in rats

Acta Neuropathologica, 2004

Macrophage migration inhibitory factor (MIF) is a multipotential protein that acts as a pro-infla... more Macrophage migration inhibitory factor (MIF) is a multipotential protein that acts as a pro-inflammatory cytokine, pituitary hormone, immunoregulator, and mitogen. To elucidate function of MIF in spinal cord injury, we examined expression of MIF after compression-induced spinal cord injury using Northern blot analysis, in situ hybridization and immunohistochemistry. The MIF mRNA was up-regulated in injured spinal cord, peaking 3 days after injury shown by Northern blot analysis. In situ hybridization revealed up-regulation of MIF in microglia accumulating in the lesion epicenter 3 days after injury and astrocytes around the cystic cavity 1 week after injury. Double staining showed co-localization of MIF and tomato lectin in the lesioned site, indicating that microglia accumulating to the lesion epicenter express MIF. The time course of MIF expression is different from that of previous reports about cytokine expression peaking at earlier time points; thus, it is unlikely that MIF acts as a pro-inflammatory factor in the present study. The MIF may contribute to proliferation of astrocytes around the lesioned site in spinal cord injury because of its cell proliferation-promoting property.

AANG Prevents Smad3-dependent Diabetic Nephropathy by Restoring Pancreatic β-Cell Development in db/db Mice

International Journal of Biological Sciences

Diabetic nephropathy (DN) is a major cause of end-stage kidney disease, where TGF-β1/Smad signali... more Diabetic nephropathy (DN) is a major cause of end-stage kidney disease, where TGF-β1/Smad signaling plays an important role in the disease progression. Our previous studies demonstrated a combination of Traditional Chinese Medicine derived Smad7 agonist Asiatic Acid (AA) and Smad3 inhibitor Naringenin (NG), AANG, effectively suppressed the progression of renal fibrosis in vivo. However, its implication in type-2 diabetic nephropathy (T2DN) is still unexplored. Here, we detected progressive activation of Smad3 but reduction of Smad7 in db/db mice during T2DN development. Therefore, we optimized the dosage and the combination ratio of AANG to achieve a better rebalancing Smad3/Smad7 signaling for treatment of T2DN. Unexpectedly, preventive treatment with combined AANG from week 4 before the development of diabetes and T2DN effectively protected against the onset of T2DN. In contract, these inhibitory effects were lost when db/db mice received the late AANG treatment from 12-24 weeks. Surprisingly, preventive treatment with AANG ameliorated not only T2DN but also the primary disease type-2 diabetes (T2D) with relative normal levels of fasting blood glucose and HbA1c, and largely improving metabolic abnormalities especially on insulin insensitivity and glucose tolerance in db/db mice. Mechanistically, AANG effectively prevented both Smad3-mediated renal fibrosis and NF-κB-driven renal inflammation in the diabetic kidney in vivo and advanced glycation end-products (AGE) stimulated tubular epithelial mTEC cells in vitro. More importantly, we uncovered that preventive treatment with AANG effectively protected against diabetic-associated islet injury via restoring the β cell development in db/db mice. Taken together, we discovered that the early treatment with combined AANG can effectively protect against the development of T2D and T2DN via mechanism associated with protection against Smad3-depenedent islet injury.

Novel lncRNA Erbb4-IR Promotes Diabetic Kidney Injury in db/db Mice by Targeting miR-29b

Diabetes, Apr 8, 2017

TGF-β/Smad signaling plays an important role in diabetic nephropathy. The present study identifie... more TGF-β/Smad signaling plays an important role in diabetic nephropathy. The present study identified a novel Smad3-dependent long non-coding RNA (lncRNA) Erbb4-IR in the development of type-2 diabetic nephropathy (T2DN) in db/db mice. We found that Erbb4-IR was highly expressed in T2DN of db/db mice and was specifically induced by AGE via a Smad3-dependent mechanism. The functional role of Erbb4-IR in T2DN was revealed by kidney-specific silencing of Erbb4-IR to protect against the development of T2DN such as elevated microalbuminuria, serum creatinine and progressive renal fibrosis in db/db mice, and to block AGE-induced collagen I and IV expression in mouse mesangial cells (mMCs) and mouse tubular epithelial cells (mTECs). Mechanistically, we identified that the Erbb4-IR-miR-29b axis was a key mechanism of T2DN because Erbb4-IR was able to bind the 3'UTR of miR-29b genomic sequence to suppress miR-29b expression at transcriptional level. In contrast, silencing of renal Erbb4-IR ...

CXCL9, but not CXCL10, Promotes CXCR3-Dependent Immune-Mediated Kidney Disease

Journal of the American Society of Nephrology, 2008

Chemokines are instrumental in macrophage-and T cell-dependent diseases. The chemokine CCL2 promo... more Chemokines are instrumental in macrophage-and T cell-dependent diseases. The chemokine CCL2 promotes kidney disease in two models of immune-mediated nephritis (MRL-Fas lpr mice and the nephrotoxic serum nephritis model), but evidence suggests that multiple chemokines are involved. For identification of additional therapeutic targets for immune-mediated nephritis, chemokine ligands and receptors in CCL2 Ϫ/Ϫ and wild-type (WT) MRL-Fas lpr kidneys were profiled. The focus was on intrarenal chemokine ligand/receptor pairs that were highly upregulated downstream of CCL2; the chemokine CXCL10 and its cognate receptor, CXCR3, stood out as potential therapeutic targets. However, renal disease was not suppressed in CXCL10 Ϫ/Ϫ MRL-Fas lpr mice, and CXCL10 Ϫ/Ϫ C57BL/6 mice were not protected from nephrotoxic serum nephritis compared with WT mice. Because CXCR3 engages with the ligand CXCL9, CXCR3 Ϫ/Ϫ , CXCL9 Ϫ/Ϫ , and CXCL10 Ϫ/Ϫ B6 mice were compared with WT mice with nephrotoxic serum nephritis. Kidney disease, measured by loss of renal function and histopathology, was suppressed in both CXCR3 Ϫ/Ϫ and CXCL9 Ϫ/Ϫ mice but not in CXCL10 Ϫ/Ϫ mice. With nephrotoxic serum nephritis, CXCR3 Ϫ/Ϫ and CXCL9 Ϫ/Ϫ mice had fewer intrarenal activated T cells and activated macrophages. Both IgG glomerular deposits and antigen-specific IgG in serum were reduced in these mice, suggesting that although CXCR3 and CXCL9 initiate nephritis through cell-mediated events, renal inflammation may be sustained by their regulation of IgG. It is concluded that specific blockade of CXCL9 or CXCR3 may be a potential therapeutic target for human immune-mediated kidney diseases.