Aggravated renal injury through HMGB1 upon TLR2/IL-1β inflammatory pathway in STZ-induced diabetic mice

Abstract Diabetic kidney disease (DKD) is the major cause of end-stage renal disease and is closely associated with the inflammation. The aim of this study was to investigate the involvement of HMGB upon TLR2/IL-1β signaling pathway in diabetic renal injury. After intraperitoneal injection of STZ for wo consecutive days, mice developed DKD companying with remarkable renal injury, manifested with albuminuria and renal histological characteristics. In the kidney, the expressions of HMGB1, TLR2 and p-NF-κB were obviously increased, and the levels of TNF-α and IL-6 were significantly higher in DKD mice than that in normal mice. The infiltration of macrophages demonstrated by high stain of F4/80 and CD14 in the kidney of DKD mice. Furthermore, fibrosis related marker of Collagen IV, fibronectin and TGF-β1 showed highly expressions and accumulated in the kidney of DKD mice. In vitro, HMGB-mediated inflammatory pathway was activated in HMGB1/IL-1β-treated HK-2 cell, while C29 (a TLR2 inhibitor) could inhibited the HMGB1 expression. The result indicated that HMGB1-mediated TLR2/IL-1β signaling pathways facilitated macrophage recruitment and fibroblast proliferation, which resulting in a positive feedback to sustain a self-perpetuating cycle of renal inflammation. Therefore, HMGB1 might be a potential target in DKD therapeutic interventions.

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Regulatory T-cells and their impacts on cytokine profile of end-stage renal disease patients suffering from systemic lupus erythematosus

International Journal of Immunopathology and Pharmacology ◽

10.1177/2058738419863238 ◽

2019 ◽

Vol 33 ◽

pp. 205873841986323 ◽

Cited By ~ 1

Author(s):

Farshid Fathi ◽

Abdolamir Atapour ◽

Nahid Eskandari ◽

Niloufar Keyhanmehr ◽

Hossein Hafezi ◽

...

Keyword(s):

Blood Transfusion ◽

Lupus Erythematosus ◽

Healthy Subjects ◽

Treg Number ◽

Tnf Α ◽

Ifn Γ ◽

Stage Renal Disease ◽

End Stage ◽

Esrd Patients ◽

Tgf Β1

Autoimmunity is an identified factor for development of end-stage renal disease (ESRD). Regulatory T-cells (Tregs) play a fundamental role in preventing autoimmunity. This study aimed to determine Treg frequency and its effects on cytokine profile of ESRD patients with and without systemic lupus erythematosus (SLE). Moreover, this study also determines how Treg number is affected by blood transfusion and gender. Peripheral blood mononuclear cells were isolated from 26 ESRD and 10 healthy subjects and stained with anti-CD4, anti-CD25, and anti-FoxP3 antibodies. Treg frequencies in ESRD patients with and without blood transfusion were determined by flow cytometry. Antibodies against human leukocyte antigens (HLAs) were investigated by panel-reactive antibodies screening. Tumor growth factor (TGF)-β1, interleukin (IL)-4, IL-10, TNF-α, IL-17A, and interferon (IFN)-γ serum levels in participants were measured by enzyme-linked immunoasorbent assay (ELISA). ESRD patients with SLE, unlike the patients without SLE, showed a significant reduction in Treg percentage compared to healthy subjects ( P < 0.01). All women had a reduced number of Tregs compared to men. Treg number was significantly decreased in ESRD patients with HLA antibodies ( P < 0.05). Blood transfusion enhanced Treg development in ESRD patients without SLE, unlike the patients with SLE ( P < 0.05). ESRD patients with low Treg showed a reduction in TGF-β1 and IL-4 and an increase in TNF-α and IL-17A levels compared to control groups ( P < 0.05–0.0001). However, no change was observed in IL-10 and IFN-γ levels. Treg frequency was negatively associated with the age of patients ( P < 0.01), while this association was not observed in healthy subjects. Based on these findings, it can be observed that reduction in Treg number may contribute to ESRD development in patients with SLE.

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A therapeutic vascular conduit to support in vivo cell-secreted therapy

npj Regenerative Medicine ◽

10.1038/s41536-021-00150-2 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Edward X. Han ◽

Hong Qian ◽

Bo Jiang ◽

Maria Figetakis ◽

Natalia Kosyakova ◽

...

Keyword(s):

Vascular Graft ◽

Large Scale ◽

Biological Effects ◽

Therapeutic Protein ◽

Close Proximity ◽

Delivery Platform ◽

Stage Renal Disease ◽

End Stage

AbstractA significant barrier to implementation of cell-based therapies is providing adequate vascularization to provide oxygen and nutrients. Here we describe an approach for cell transplantation termed the Therapeutic Vascular Conduit (TVC), which uses an acellular vessel as a scaffold for a hydrogel sheath containing cells designed to secrete a therapeutic protein. The TVC can be directly anastomosed as a vascular graft. Modeling supports the concept that the TVC allows oxygenated blood to flow in close proximity to the transplanted cells to prevent hypoxia. As a proof-of-principle study, we used erythropoietin (EPO) as a model therapeutic protein. If implanted as an arteriovenous vascular graft, such a construct could serve a dual role as an EPO delivery platform and hemodialysis access for patients with end-stage renal disease. When implanted into nude rats, TVCs containing EPO-secreting fibroblasts were able to increase serum EPO and hemoglobin levels for up to 4 weeks. However, constitutive EPO expression resulted in macrophage infiltration and luminal obstruction of the TVC, thus limiting longer-term efficacy. Follow-up in vitro studies support the hypothesis that EPO also functions to recruit macrophages. The TVC is a promising approach to cell-based therapeutic delivery that has the potential to overcome the oxygenation barrier to large-scale cellular implantation and could thus be used for a myriad of clinical disorders. However, a complete understanding of the biological effects of the selected therapeutic is absolutely essential.

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Uremic Toxins and Their Relation with Oxidative Stress Induced in Patients with CKD

International Journal of Molecular Sciences ◽

10.3390/ijms22126196 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6196

Author(s):

Anna Pieniazek ◽

Joanna Bernasinska-Slomczewska ◽

Lukasz Gwozdzinski

Keyword(s):

Oxidative Stress ◽

Uremic Toxins ◽

Water Medium ◽

Induce Insulin Resistance ◽

Risk Of Mortality ◽

Increased Risk ◽

Stage Renal Disease ◽

End Stage

The presence of toxins is believed to be a major factor in the development of uremia in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Uremic toxins have been divided into 3 groups: small substances dissolved in water, medium molecules: peptides and low molecular weight proteins, and protein-bound toxins. One of the earliest known toxins is urea, the concentration of which was considered negligible in CKD patients. However, subsequent studies have shown that it can lead to increased production of reactive oxygen species (ROS), and induce insulin resistance in vitro and in vivo, as well as cause carbamylation of proteins, peptides, and amino acids. Other uremic toxins and their participation in the damage caused by oxidative stress to biological material are also presented. Macromolecules and molecules modified as a result of carbamylation, oxidative stress, and their adducts with uremic toxins, may lead to cardiovascular diseases, and increased risk of mortality in patients with CKD.

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Therapeutic Strategies for Diabetic Kidney Disease

Diabetology ◽

10.3390/diabetology2010003 ◽

2021 ◽

Vol 2 (1) ◽

pp. 31-35

Author(s):

Keiichiro Matoba

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Intensive Therapy ◽

Therapeutic Strategies ◽

Therapeutic Interventions ◽

Hemodynamic Changes ◽

Diabetic Kidney ◽

Global Epidemic ◽

Stage Renal Disease ◽

End Stage

Diabetic kidney disease (DKD) is a global epidemic leading to end-stage renal disease (ESRD) and susceptibility to cardiovascular disease, with few therapeutic interventions. A hallmark of DKD is the activation of the renin-angiotensin-aldosterone system and hemodynamic changes in glomerulus. Although intensive therapy with agents that targets those abnormalities lowers the risk of DKD progression, it does not completely abolish the risk of ESRD and cardiovascular events. Recent studies have illustrated the importance of renal inflammation, oxidative stress, and activated Rho-associated protein kinase (ROCK) signaling as essential pathogenesis for the development of DKD. In this commentary, these topics will be discussed.

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Identification of a microRNA signature in renal fibrosis: role of miR-21

AJP Renal Physiology ◽

10.1152/ajprenal.00273.2011 ◽

2011 ◽

Vol 301 (4) ◽

pp. F793-F801 ◽

Cited By ~ 169

Author(s):

Abolfazl Zarjou ◽

Shanzhong Yang ◽

Edward Abraham ◽

Anupam Agarwal ◽

Gang Liu

Keyword(s):

Epithelial Cells ◽

Renal Fibrosis ◽

Transforming Growth Factor ◽

Response To Treatment ◽

Tubular Epithelial Cells ◽

Altered Expression ◽

Tnf Α ◽

Tgf Β1

Renal fibrosis is a final stage of many forms of kidney disease and leads to impairment of kidney function. The molecular pathogenesis of renal fibrosis is currently not well-understood. microRNAs (miRNAs) are important players in initiation and progression of many pathologic processes including diabetes, cancer, and cardiovascular disease. However, the role of miRNAs in kidney injury and repair is not well-characterized. In the present study, we found a unique miRNA signature associated with unilateral ureteral obstruction (UUO)-induced renal fibrosis. We found altered expression in UUO kidneys of miRNAs that have been shown to be responsive to stimulation by transforming growth factor (TGF)-β1 or TNF-α. Among these miRNAs, miR-21 demonstrated the greatest increase in UUO kidneys. The enhanced expression of miR-21 was located mainly in distal tubular epithelial cells. miR-21 expression was upregulated in response to treatment with TGF-β1 or TNF-α in human renal tubular epithelial cells in vitro. Furthermore, we found that blocking miR-21 in vivo attenuated UUO-induced renal fibrosis, presumably through diminishing the expression of profibrotic proteins and reducing infiltration of inflammatory macrophages in UUO kidneys. Our data suggest that targeting specific miRNAs could be a novel therapeutic approach to treat renal fibrosis.

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High Matrix Metalloproteinase Production Correlates with Immune Activation and Leukocyte Migration in Leprosy Reactional Lesions

Infection and Immunity ◽

10.1128/iai.00896-09 ◽

2009 ◽

Vol 78 (3) ◽

pp. 1012-1021 ◽

Cited By ~ 17

Author(s):

Rosane M. B. Teles ◽

Rose B. Teles ◽

Thais P. Amadeu ◽

Danielle F. Moura ◽

Leila Mendonça-Lima ◽

...

Keyword(s):

Matrix Metalloproteinase ◽

Cultured Cells ◽

Leukocyte Migration ◽

Therapeutic Interventions ◽

Matrix Metalloproteinase 2 ◽

Mrna Levels ◽

Membrane Breakdown ◽

Tnf Α ◽

Ifn Γ

ABSTRACT Gelatinases A and B (matrix metalloproteinase 2 [MMP-2] and MMP-9, respectively) can induce basal membrane breakdown and leukocyte migration, but their role in leprosy skin inflammation remains unclear. In this study, we analyzed clinical specimens from leprosy patients taken from stable, untreated skin lesions and during reactional episodes (reversal reaction [RR] and erythema nodosum leprosum [ENL]). The participation of MMPs in disease was suggested by (i) increased MMP mRNA expression levels in skin biopsy specimens correlating with the expression of gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α), (ii) the detection of the MMP protein and enzymatic activity within the inflammatory infiltrate, (iii) increased MMP levels in patient sera, and (iv) the in vitro induction of MMP-9 by Mycobacterium leprae and/or TNF-α. It was observed that IFN-γ, TNF-α, MMP-2, and MMP-9 mRNA levels were higher in tuberculoid than lepromatous lesions. In contrast, interleukin-10 and tissue inhibitor of MMP (TIMP-1) message were not differentially modulated. These data correlated with the detection of the MMP protein evidenced by immunohistochemistry and confocal microscopy. When RR and ENL lesions were analyzed, an increase in TNF-α, MMP-2, and MMP-9, but not TIMP-1, mRNA levels was observed together with stronger MMP activity (zymography/in situ zymography). Moreover, following in vitro stimulation of peripheral blood cells, M. leprae induced the expression of MMP-9 (mRNA and protein) in cultured cells. Overall, the present data demonstrate an enhanced MMP/TIMP-1 ratio in the inflammatory states of leprosy and point to potential mechanisms for tissue damage. These results pave the way toward the application of new therapeutic interventions for leprosy reactions.

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Centrifugation Conditions in the L-PRP Preparation Affect Soluble Factors Release and Mesenchymal Stem Cell Proliferation in Fibrin Nanofibers

Molecules ◽

10.3390/molecules24152729 ◽

2019 ◽

Vol 24 (15) ◽

pp. 2729 ◽

Cited By ~ 4

Author(s):

Melo ◽

Luzo ◽

Lana ◽

Santana

Keyword(s):

Growth Factor ◽

Transforming Growth Factor ◽

Platelet Rich Plasma ◽

Clinical Practices ◽

Soluble Factors ◽

Tnf Α ◽

Platelet Concentration ◽

Tgf Β1

Leukocyte and platelet-rich plasma (L-PRP) is an autologous product that when activated forms fibrin nanofibers, which are useful in regenerative medicine. As an important part of the preparation of L-PRP, the centrifugation parameters may affect the release of soluble factors that modulate the behavior of the cells in the nanofibers. In this study, we evaluated the influences of four different centrifugation conditions on the concentration of platelets and leukocytes in L-PRP and on the anabolic/catabolic balance of the nanofiber microenvironment. Human adipose-derived mesenchymal stem cells (h-AdMSCs) were seeded in the nanofibers, and their viability and growth were evaluated. L-PRPs prepared at 100× g and 100 + 400× g released higher levels of transforming growth factor (TGF)-β1 and platelet-derived growth factor (PDGF)-BB due to the increased platelet concentration, while inflammatory cytokines interleukin (IL)-8 and tumor necrosis factor (TNF)-α were more significantly released from L-PRPs prepared via two centrifugation steps (100 + 400× g and 800 + 400× g) due to the increased concentration of leukocytes. Our results showed that with the exception of nanofibers formed from L-PRP prepared at 800 + 400× g, all other microenvironments were favorable for h-AdMSC proliferation. Here, we present a reproducible protocol for the standardization of L-PRP and fibrin nanofibers useful in clinical practices with known platelet/leukocyte ratios and in vitro evaluations that may predict in vivo results.

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An Exosomal Urinary miRNA Signature for Early Diagnosis of Renal Fibrosis in Lupus Nephritis

Cells ◽

10.3390/cells8080773 ◽

2019 ◽

Vol 8 (8) ◽

pp. 773 ◽

Cited By ~ 15

Author(s):

Solé ◽

Moliné ◽

Vidal ◽

Ordi-Ros ◽

Cortés-Hernández

Keyword(s):

Lupus Nephritis ◽

Renal Fibrosis ◽

Target Genes ◽

Early Stage ◽

High Sensitivity ◽

Increased Risk ◽

Chronicity Index ◽

Stage Renal Disease ◽

End Stage

For lupus nephritis (LN) management, it is very important to detect fibrosis at an early stage. Urinary exosomal miRNAs profiling can be used as a potential multi-marker phenotyping tool to identify early fibrosis. We isolated and characterised urinary exosomes and cellular pellets from patients with biopsy-proven LN (n = 45) and healthy controls (n = 20). LN chronicity index (CI) correlated with urinary exosomal miR-21, miR-150, and miR-29c (r = 0.565, 0.840, −0.559, respectively). This miRNA profile distinguished low CI from moderate-high CI in LN patients with a high sensitivity and specificity (94.4% and 99.8%). Furthermore, this multimarker panel predicted an increased risk of progression to end-stage renal disease (ESRD). Pathway analysis identified VEGFA and SP1 as common target genes for the three miRNAs. Immunohistochemistry in LN renal biopsies revealed a significant increase of COL1A1 and COL4A1 correlated with renal chronicity. SP1 decreased significantly in the high-CI group (p = 0.002). VEGFA levels showed no differences. In vitro experiments suggest that these miRNA combinations promote renal fibrosis by increasing profibrotic molecules through SP1 and Smad3/TGFβ pathways. In conclusion, a urinary exosomal multimarker panel composed of miR-21, miR-150, and miR-29c provides a non-invasive method to detect early renal fibrosis and predict disease progression in LN.

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An Overview of In Vivo and In Vitro Models for Autosomal Dominant Polycystic Kidney Disease: A Journey from 3D-Cysts to Mini-Pigs

International Journal of Molecular Sciences ◽

10.3390/ijms21124537 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4537

Author(s):

Svenja Koslowski ◽

Camille Latapy ◽

Pierrïck Auvray ◽

Marc Blondel ◽

Laurent Meijer

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Autosomal Dominant ◽

In Vitro Models ◽

Polycystic Kidney ◽

Autosomal Dominant Polycystic Kidney ◽

Stage Renal Disease ◽

End Stage

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inheritable cause of end stage renal disease and, as of today, only a single moderately effective treatment is available for patients. Even though ADPKD research has made huge progress over the last decades, the precise disease mechanisms remain elusive. However, a wide variety of cellular and animal models have been developed to decipher the pathophysiological mechanisms and related pathways underlying the disease. As none of these models perfectly recapitulates the complexity of the human disease, the aim of this review is to give an overview of the main tools currently available to ADPKD researchers, as well as their main advantages and limitations.

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In-Vitro Evaluation of an UL TRA Violet Germicidal Connection System for CAPD

Peritoneal Dialysis International ◽

10.1177/089686088400400407 ◽

1984 ◽

Vol 4 (4) ◽

pp. 215-218 ◽

Cited By ~ 9

Author(s):

Clifford J. Holmes ◽

Cynthia Miyake ◽

Winnie Kubey

Keyword(s):

Microbial Population ◽

Uv Light ◽

Second Phase ◽

Membrane Filters ◽

Connection System ◽

Fluid Transfer ◽

Stage Renal Disease ◽

End Stage ◽

Welding Technique

We have evaluated UV irradiation of the setlbag connection as a method of eliminating organisms causing peritonitis among CAPD patients. In the first phase of the study, spike lumens of CAPD transfer sets were inoculated with C. albicans, which are known to be relatively resistant to UV light. After irradiation, results showed a 61og 10 reduction in microbial population. In the second phase, the spikes were contaminated by touch. Following irradiation, 100% of the contaminated spikes were disinfected. These data indicate that UV germicidal systems can achieve a significant reduction of contaminating microbial population on a CAPD transfer-set spike. Continuous ambulatory peritoneal dialysis (CAPD) is now a well-accepted therapy for end-stage renal disease (I). However, peritonitis remains a potential complication of this therapy. Several methods have been proposed for preventing microorganisms from entering the peritoneum via the primary (set-to-bag) connection. Such approaches have included placement of membrane filters in the fluid transfer set (2), use of disinfectant solutions (3), and recently the “sterile welding” technique (4). A gennicidal system, which uses ultraviolet (UV) light as the disinfecting source, has recently become available. Ultraviolet light has beeen utilized in industry and medicine for a number of years and for a number of applications, e.g., disinfecting operating rooms (5) and sterilizing water and packaging materials (6). The present paper describes the evaluation of ultraviolet irradiation as a means of disinfecting the CAPD transfer set-to-bag connection.

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