scholarly journals ALW peptide ameliorates lupus nephritis in MRL/lpr mice

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Huixia Wang ◽  
Mei Lu ◽  
Siyue Zhai ◽  
Kunyi Wu ◽  
Lingling Peng ◽  
...  
Keyword(s):  
Growth Factor ◽  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Kidney Tissue ◽  
Inflammatory Cells ◽  
Blank Group ◽  
Histopathologic Changes

Abstract Background Lupus nephritis (LN) is a common and serious complication of systemic lupus erythematosus. Anti-double-stranded (ds) DNA immunoglobulin G (IgG) plays a pivotal role in the pathogenesis of LN. Currently, there are various therapies for patients with LN; however, most of them are associated with considerable side effects. We confirmed previously that ALW (ALWPPNLHAWVP), a 12-amino acid peptide, inhibited the binding of polyclonal anti-dsDNA antibodies to mesangial cells and isolated glomeruli in vitro. In this study, we further investigate whether the administration of ALW peptide decreases renal IgG deposition and relevant damage in MRL/lpr lupus-prone mice. Methods Forty female MRL/lpr mice were randomly divided into four groups. The mice were intravenously injected with D-form ALW peptide (ALW group), scrambled peptide (PLP group), and normal saline (NaCl group) or were not treated (blank group). The IgG deposition, the histopathologic changes, and the expressions of profibrotic factors were analyzed in the kidney of MRL/lpr mice. Results Compared with the other groups, glomerular deposition of IgG, IgG2a, IgG2b, and IgG3 was decreased in the ALW group. Moreover, ALW administration attenuated renal histopathologic changes in MRL/lpr mice, including mesangial proliferation and infiltration of inflammatory cells. Furthermore, the expressions of profibrotic cytokines, such as transforming growth factor-beta1 (TGF-β1) and platelet-derived growth factor B (PDGF-B), decreased in the serum and kidney tissue of ALW-treated mice. Conclusions Our study demonstrated that ALW peptide ameliorates the murine model of LN, possibly through inhibiting renal IgG deposition and relevant tissue inflammation and fibrosis.

scholarly journals Quantitative planar array screen of 1000 proteins uncovers novel urinary protein biomarkers of lupus nephritis

2020 ◽  
Vol 79 (10) ◽  
pp. 1349-1361
Author(s):  
Kamala Vanarsa ◽  
Sanam Soomro ◽  
Ting Zhang ◽  
Briony Strachan ◽  
Claudia Pedroza ◽  
...  
Keyword(s):  
Growth Factor ◽  
Lupus Nephritis ◽  
Disease Activity ◽  
Single Cell ◽  
Rna Sequencing ◽  
Lupus Erythematosus ◽  
Transforming Growth Factor ◽  
Sequencing Analysis ◽  
Potential Biomarker ◽  
Planar Array

ObjectiveThe goal of these studies is to discover novel urinary biomarkers of lupus nephritis (LN).MethodsUrine from systemic lupus erythematosus (SLE) patients was interrogated for 1000 proteins using a novel, quantitative planar protein microarray. Hits were validated in an independent SLE cohort with inactive, active non-renal (ANR) and active renal (AR) patients, in a cohort with concurrent renal biopsies, and in a longitudinal cohort. Single-cell renal RNA sequencing data from LN kidneys were examined to deduce the cellular origin of each biomarker.ResultsScreening of 1000 proteins revealed 64 proteins to be significantly elevated in SLE urine, of which 17 were ELISA validated in independent cohorts. Urine Angptl4 (area under the curve (AUC)=0.96), L-selectin (AUC=0.86), TPP1 (AUC=0.84), transforming growth factor-β1 (TGFβ1) (AUC=0.78), thrombospondin-1 (AUC=0.73), FOLR2 (AUC=0.72), platelet-derived growth factor receptor-β (AUC=0.67) and PRX2 (AUC=0.65) distinguished AR from ANR SLE, outperforming anti-dsDNA, C3 and C4, in terms of specificity, sensitivity and positive predictive value. In multivariate regression analysis, urine Angptl4, L-selectin, TPP1 and TGFβ1 were highly associated with disease activity, even after correction for demographic variables. In SLE patients with serial follow-up, urine L-selectin (followed by urine Angptl4 and TGFβ1) were best at tracking concurrent or pending disease flares. Importantly, several proteins elevated in LN urine were also expressed within the kidneys in LN, either within resident renal cells or infiltrating immune cells, based on single-cell RNA sequencing analysis.ConclusionUnbiased planar array screening of 1000 proteins has led to the discovery of urine Angptl4, L-selectin and TGFβ1 as potential biomarker candidates for tracking disease activity in LN.

Suppressions of chronic glomerular injuries and TGF-β1 production by HGF in attenuation of murine diabetic nephropathy

2004 ◽  
Vol 286 (1) ◽  
pp. F134-F143 ◽  
Author(s):  
Shinya Mizuno ◽  
Toshikazu Nakamura
Keyword(s):  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Renal Dysfunction ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Renal Diseases ◽  
Glomerular Mesangial Cells ◽  
Diabetic Mice

Diabetic nephropathy is now the leading cause of end-stage renal diseases, and glomerular sclerotic injury is an initial event that provokes renal dysfunction during processes of diabetes-linked kidney disease. Growing evidence shows that transforming growth factor-β1 (TGF-β1) plays a key role in this process, especially in eliciting hypertrophy and matrix overaccumulation. Thus it is important to find a ligand system to antagonize the TGF-β1-mediated pathogenesis under high-glucose conditions. Herein, we provide evidence that hepatocyte growth factor (HGF) targets mesangial cells, suppresses TGF-β1 production, and minimizes glomerular sclerotic changes, using streptozotocin-induced diabetic mice. In our murine model, glomerular sclerogenesis (such as tuft area expansion and collagen deposition) progressed between 6 and 10 wk after the induction of hyperglycemia, during a natural course of diabetic disease. Glomerular HGF expression levels in the diabetic kidney transiently increased but then declined below a basal level, with manifestation of glomerular sclerogenesis. When anti-HGF IgG was injected into mice for 2 wk (i.e., from weeks 4 to 6 after onset of hyperglycemia), these glomerular changes were significantly aggravated. When recombinant HGF was injected into the mice for 4 wk (i.e., between 6 and 10 wk following streptozotocin treatment), the progression of glomerular hypertrophy and sclerosis was almost completely inhibited, even though glucose levels remained unchanged (>500 mg/dl). Even more important, HGF repressed TGF-β1 production in glomerular mesangial cells even under hyperglycemic conditions both in vitro and in vivo. Consequently, not only albuminuria but also tubulointerstitial fibrogenesis were attenuated by HGF. Overall, HGF therapy inhibited the onset of renal dysfunction in the diabetic mice. On the basis of these findings, we wish to emphasize that HGF plays physiological and therapeutic roles in blocking renal fibrogenesis during a course of diabetic nephropathy.

scholarly journals Mesangial cells are key contributors to the fibrotic damage seen in the lupus nephritis glomerulus

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Rachael D. Wright ◽  
Paraskevi Dimou ◽  
Sarah J. Northey ◽  
Michael W. Beresford
Keyword(s):  
Lupus Nephritis ◽  
Inflammatory Cytokines ◽  
Lupus Erythematosus ◽  
In Vitro Model ◽  
Mesangial Cells ◽  
Vitro Model ◽  
Tgf Β1 ◽  
Onset Systemic Lupus Erythematosus ◽  
Pro Inflammatory Cytokines

Abstract Background Lupus nephritis (LN) affects up to 80% of juvenile-onset systemic lupus erythematosus patients. Mesangial cells (MCs) comprise a third of the glomerular cells and are key contributors to fibrotic changes within the kidney. This project aims to identify the roles of MCs in an in vitro model of LN. Methods Conditionally immortalised MCs were treated with pro-inflammatory cytokines or with patient sera in an in vitro model of LN and assessed for their roles in inflammation and fibrosis. Results MCs were shown to produce pro-inflammatory cytokines in response to a model of the inflammatory environment in LN. Further the cells expressed increased levels of mRNA for extracellular matrix (ECM) proteins (COL1A1, COL1A2, COL4A1 and LAMB1), matrix metalloproteinase enzymes (MMP9) and tissue inhibitors of matrix metalloproteinases (TIMP1). Treatment of MCs with serum from patients with active LN was able to induce a similar, albeit milder phenotype. Treatment of MCs with cytokines or patient sera was able to induce secretion of TGF-β1, a known inducer of fibrotic changes. Inhibition of TGF-β1 actions through SB-431542 (an activin A receptor type II-like kinase (ALK5) inhibitor) was able to reduce these responses suggesting that the release of TGF-β1 plays a role in these changes. Conclusions MCs contribute to the inflammatory environment in LN by producing cytokines involved in leukocyte recruitment, activation and maturation. Further the cells remodel the ECM via protein deposition and enzymatic degradation. This occurs through the actions of TGF-β1 on its receptor, ALK5. This may represent a potential therapeutic target for treatment of LN-associated fibrosis.

scholarly journals Inhibition of transforming growth factor-β signaling in myeloid cells ameliorates aortic aneurysmal formation in Marfan syndrome

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0239908
Author(s):  
Hironori Hara ◽  
Sonoko Maemura ◽  
Takayuki Fujiwara ◽  
Norifumi Takeda ◽  
Satoshi Ishii ◽  
...  
Keyword(s):  
Growth Factor ◽  
Marfan Syndrome ◽  
Transforming Growth Factor ◽  
Receptor Gene ◽  
Myeloid Cells ◽  
Inflammatory Cells ◽  
Transforming Growth Factor Β ◽  
Elastic Fibers ◽  
Raw264.7 Macrophages

Increased transforming growth factor-β (TGF-β) signaling contributes to the pathophysiology of aortic aneurysm in Marfan syndrome (MFS). Recent reports indicate that a small but significant number of inflammatory cells are infiltrated into the aortic media and adventitia in MFS. However, little is known about the contribution of myeloid cells to aortic aneurysmal formation. In this study, we ablated the TGF-β type II receptor gene Tgfbr2 in myeloid cells of Fbn1C1039G/+ MFS mice (Fbn1C1039G/+;LysM-Cre/+;Tgfbr2fl/fl mice, hereinafter called Fbn1C1039G/+;Tgfbr2MyeKO) and evaluated macrophage infiltration and TGF-β signaling in the aorta. Aneurysmal formation with fragmentation and disarray of medial elastic fibers observed in MFS mice was significantly ameliorated in Fbn1C1039G/+;Tgfbr2MyeKO mice. In the aorta of Fbn1C1039G/+;Tgfbr2MyeKO mice, both canonical and noncanonical TGF-β signals were attenuated and the number of infiltrated F4/80-positive macrophages was significantly reduced. In vitro, TGF-β enhanced the migration capacity of RAW264.7 macrophages. These findings suggest that TGF-β signaling in myeloid cells promotes aortic aneurysmal formation and its inhibition might be a novel therapeutic target in MFS.

Characterization of a putative intrarenal serotonergic system

2007 ◽  
Vol 293 (5) ◽  
pp. F1468-F1475 ◽  
Author(s):  
Jie Xu ◽  
Bing Yao ◽  
Xiaofeng Fan ◽  
Melissa M. Langworthy ◽  
Ming-Zhi Zhang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Tissue Growth ◽  
Serotonergic System ◽  
Rt Pcr

Serotonin [5-hydroxytryptamine (5HT)] acts through multiple G protein-coupled 5-HT receptors, and its activity is also regulated by the 5-HT transporter. The current studies report the expression and localization of the 5-HT receptors and transporter in the kidney. In addition, the enzymatic pathway mediating 5-HT synthesis is present in renal cortex, especially in the proximal tubules and glomerular epithelial cells and mesangial cells. Expression of the 5-HT receptors and 5-HT transporter was detected by RT-PCR in cell lines of these cell types. In cultured proximal tubule cells and podocytes, 5-HT activated ERK1/2 and increased the expression of connective tissue growth factor and transforming growth factor-β, two key mediators of extracellular matrix accumulation. Immunohistochemistry and real-time RT-PCR studies also indicated that 5-HT stimulated expression of vascular endothelial growth factor in podocytes in vitro and in vivo. Therefore, these results indicate the presence of an integrated intrarenal serotonergic system and suggest a possible role for 5-HT as a mediator of renal fibrosis in the kidney.

scholarly journals Telocinobufagin, a Novel Cardiotonic Steroid, Promotes Renal Fibrosis via Na+/K+-ATPase Profibrotic Signaling Pathways

2018 ◽  
Vol 19 (9) ◽  
pp. 2566 ◽  
Author(s):  
David Kennedy ◽  
Fatimah Khalaf ◽  
Brendan Sheehy ◽  
Malory Weber ◽  
Brendan Agatisa-Boyle ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Growth Factor ◽  
Kidney Disease ◽  
Renal Dysfunction ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Src Kinase ◽  
Tissue Growth

Cardiotonic steroids (CTS) are Na+/K+-ATPase (NKA) ligands that are elevated in volume-expanded states and associated with cardiac and renal dysfunction in both clinical and experimental settings. We test the hypothesis that the CTS telocinobufagin (TCB) promotes renal dysfunction in a process involving signaling through the NKA α-1 in the following studies. First, we infuse TCB (4 weeks at 0.1 µg/g/day) or a vehicle into mice expressing wild-type (WT) NKA α-1, as well as mice with a genetic reduction (~40%) of NKA α-1 (NKA α-1+/−). Continuous TCB infusion results in increased proteinuria and cystatin C in WT mice which are significantly attenuated in NKA α-1+/− mice (all p < 0.05), despite similar increases in blood pressure. In a series of in vitro experiments, 24-h treatment of HK2 renal proximal tubular cells with TCB results in significant dose-dependent increases in both Collagens 1 and 3 mRNA (2-fold increases at 10 nM, 5-fold increases at 100 nM, p < 0.05). Similar effects are seen in primary human renal mesangial cells. TCB treatment (100 nM) of SYF fibroblasts reconstituted with cSrc results in a 1.5-fold increase in Collagens 1 and 3 mRNA (p < 0.05), as well as increases in both Transforming Growth factor beta (TGFb, 1.5 fold, p < 0.05) and Connective Tissue Growth Factor (CTGF, 2 fold, p < 0.05), while these effects are absent in SYF cells without Src kinase. In a patient study of subjects with chronic kidney disease, TCB is elevated compared to healthy volunteers. These studies suggest that the pro-fibrotic effects of TCB in the kidney are mediated though the NKA-Src kinase signaling pathway and may have relevance to volume-overloaded conditions, such as chronic kidney disease where TCB is elevated.

scholarly journals Mesangial cell αvβ8-integrin regulates glomerular capillary integrity and repair

2014 ◽  
Vol 306 (12) ◽  
pp. F1400-F1409 ◽  
Author(s):  
Sujata Lakhe-Reddy ◽  
Vincent Li ◽  
Thomas D. Arnold ◽  
Shenaz Khan ◽  
Jeffrey R. Schelling
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Reproductive Organs ◽  
Glomerular Injury ◽  
Rgd Peptides ◽  
Glomerular Capillary ◽  
Renal Phenotype

αvβ8-Integrin is most abundantly expressed in the kidney, brain, and female reproductive organs, and its cognate ligand is latent transforming growth factor (LTGF)-β. Kidney αvβ8-integrin localizes to mesangial cells, and global β8-integrin gene ( Itgb8) deletion results in embryonic lethality due to impaired placentation and cerebral hemorrhage. To circumvent the lethality and better define kidney αvβ8-integrin function, Cre-lox technology was used to generate mesangial-specific Itgb8-null mice. Platelet-derived growth factor-β receptor ( PDGFBR)- Cre mice crossed with a reporter strain revealed functional Cre recombinase activity in a predicted mesangial pattern. However, mating between two different PDGFBR-Cre or Ren1 d -Cre strains with Itgb8 flox/− mice consistently resulted in incomplete recombination, with no renal phenotype in mosaic offspring. Induction of a renal phenotype with Habu snake venom, a reversible mesangiolytic agent, caused exaggerated glomerular capillary microaneurysms and delayed recovery in Cre+/− PDGFRB flox/− mice compared with Cre+/− PDGFRB flox/+ control mice. To establish the mechanism, in vitro experiments were conducted in Itgb8-null versus Itgb8-expressing mesangial cells and fibroblasts, which revealed β8-integrin-regulated adhesion to Arg-Gly-Asp (RGD) peptides within a mesangial-conditioned matrix as well as β8-integrin-dependent migration on RGD-containing LTGF-β or vitronectin matrices. We speculate that kidney αvβ8-integrin indirectly controls glomerular capillary integrity through mechanical tension generated by binding RGD peptides in the mesangial matrix, and healing after glomerular injury may be facilitated by mesangial cell migration, which is guided by transient β8-integrin interactions with RGD ligands.

Correlation Between Serological Makers and Immunofluorescence Deposits i n Kidney Tissue of Patients with Lupus Nephritis

2019 ◽  
Vol 9 (02) ◽  
Author(s):  
Haider S Al-Hadad ◽  
Aqeel Abbas Matrood ◽  
Maha Abdalrasool Almukhtar ◽  
Haider Jabur Kehiosh ◽  
Riyadh Muhi Al-Saegh
Keyword(s):  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Kidney Biopsy ◽  
Pearson Correlation ◽  
Standard Procedure ◽  
Kidney Tissue ◽  
P Value ◽  
American College Of Rheumatology ◽  
Immune Deposits ◽  
Number Of Patients

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease. Few biomarkers for SLE have been validated and widely accepted for the laboratory follow-up of inflammatory activity. In SLE patients, with lupus nephritis (LN), complement activation leads to fluctuation of serum C3 and C4 that are frequently used as clinicalm biomarker of disease activity in SLE. Patients and Methods: In this study the number of patients were 37, seven patients were excluded for incomplete data collection, 28 were females ,2 were males. The duration of the study is two years from 2015 to 2017. Patients were considered to have SLE and LN according to American College of Rheumatology (ACR) criteria, and International Society of Nephrology/ Renal Pathology Society (ISN/RPS). All patients were evaluated withm clinical presentation, laboratory investigations. Our patients underwent kidney biopsy according to standard procedure by Kerstin Amann, and their tissue specimens were studied in the laboratory with light microscope (LM) and immunofluorescence microscope reagents. The relationship between the serological markers and immunofluorescence deposits in kidney biopsy of all patients were studied using the statistical analysis of Pearson correlation and single table student's T test. A P value 0.05 was considered statistically significant. Results: The granular pattern of IF deposits was present in all LN patients, and in more than two third of patients these IF deposits presented in glomerular, tubular, and mesangium sites. While less than one third of patients had IF deposits in the mesangium only. There was no statistically significant correlation between serum ANA, anti-dsDNA, and IF deposits of different types. There was significant correlation between serum C3 and C4 hypocomplementemia and IgG immune deposits in kidney biopsy, and there was significant relationship between serum C3 hypocomplementemia and full house immunofluorescence (FHIF) deposits inm kidney biopsy.Conclusions:Immunofluorescence deposits is mainly granular pattern in LN patients. There was no significant association between serum ANA, anti-dsDNA, and immune deposits in kidney tissue. Immunofluorescence deposits of IgG type correlates significantly with serum C3 and C4 hypocomplemetemia, and these immune deposits in association with low complement levels correlates with LN flare. There was significant correlation between C3 hypocomplementemia and FHIF.

A Comparative Study on the Incidence, Aggravation, and Remission of Lupus Nephritis Based on iTRAQ Technology

2020 ◽  
Vol 23 (7) ◽  
pp. 649-657
Author(s):  
Dong-Jiang Liao ◽  
Xi-Ping Cheng ◽  
Nan Li ◽  
Kang-Li Liang ◽  
Hui Fan ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Kidney Tissue ◽  
Quantitative Information ◽  
Enzyme Linked Immunosorbent Assay ◽  
Absolute Quantitation ◽  
Western Blot Method ◽  
Close Relationship ◽  
Polymerase Chain ◽  
Isobaric Tags

Aim and Objective: Lupus nephritis (LN) is one of the major complications of systemic lupus erythematosus (SLE). The specific mechanisms of pathogenesis, aggravation, and remission processes in LN have not been clarified but is of great need in the clinic. Using isobaric tags for relative and absolute quantitation (iTRAQ) technology to screen the functional proteins of LN in mice. Especially under intervention factors of lipopolysaccharide (LPS) and dexamethasone. Methods: Mrl-lps mice were intervened with LPS, dexamethasone, and normal saline (NS) using intraperitoneal injection, and c57 mice intervened with NS as control. The anti-ANA antibody enzyme-linked immunosorbent assay (ELISA) was used to verify disease severity. Kidney tissue is collected and processed for iTRAQ to screen out functional proteins closely related to the onset and development of LN. Western blot method and rt-PCR (real-time Polymerase Chain Reaction) were used for verification. Results: We identified 136 proteins that marked quantitative information. Among them, Hp, Igkv8-27, Itgb2, Got2, and Pcx proteins showed significant abnormal manifestations. Conclusion: Using iTRAQ methods, the functional proteins Hp, Igkv8-27, Itgb2, Got2, and Pcx were screened out for a close relationship with the pathogenesis and development of LN, which is worth further study.

Sign in / Sign up

Export Citation Format

Share Document