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1.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(10): 871-876, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33148380

RESUMO

Objective To investigate the effects of inorganic arsenic exposure on the differentiation of renal CD4+T lymphocytes and the possible mechanism. Methods Female C57BL/6 mice were randomly divided into control group, (2.5, 5, 10) mg/kg NaAsO2 exposure groups, 10 mice in each group. As was administered once intragastrically for 24 hours, and control mice were treated with normal saline. Real-time fluorescence quantitative PCR was used to detect T helper type 1 (Th1) cell-specific transcription factor T-box expressed in T cells (T-bet) and IFN-γ, Th2 cell-specific transcription factor GATA-binding protein 3 (GATA3) and interleukin 4 (IL-4), Th17 cell-specific transcription factor retinoic acid related orphan nuclear receptor γt (ROR-γt) and cytokine IL-22, regulatory T cells (Tregs)-specific transcription factor forkhead box P3 (FOXP3) and cytokine transforming growth factor-ß (TGF-ß) mRNA levels. We used commercial kits to detect catalase (CAT) activity and total antioxidant capacity (T-AOC) in serum as well as renal malondialdehyde (MDA) and superoxide dismutase (SOD). Results Compared with the control group, the body mass, renal mass and kidney index of the mice in all arsenic-treated groups have no significant changes. The levels of the master transcription factors T-bet, GATA3, ROR-γt and FOXP3 as well as related cytokines IFN-γ, IL-4, IL-22 and TGF-ß of Th1, Th2, Th17 cells and Tregs decreased in the arsenic-treated groups. Serum CAT activity and T-AOC level in the arsenic-treated mice dropped greatly. In addition, arsenic markedly increased renal MDA level while decreased SOD activity. Conclusion Inorganic arsenic exposure can suppress renal T cell subpopulation function and induce renal oxidative injure.


Assuntos
Arsênico/toxicidade , Rim/efeitos dos fármacos , Estresse Oxidativo , Linfócitos T Reguladores/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Animais , Citocinas/metabolismo , Feminino , Fatores de Transcrição Forkhead/metabolismo , Fator de Transcrição GATA3/metabolismo , Rim/imunologia , Camundongos , Camundongos Endogâmicos C57BL
2.
BMJ ; 371: m3734, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087345

RESUMO

OBJECTIVE: To assess whether reshaping of the immune balance by infusion of autologous natural regulatory T cells (nTregs) in patients after kidney transplantation is safe, feasible, and enables the tapering of lifelong high dose immunosuppression, with its limited efficacy, adverse effects, and high direct and indirect costs, along with addressing several key challenges of nTreg treatment, such as easy and robust manufacturing, danger of over immunosuppression, interaction with standard care drugs, and functional stability in an inflammatory environment in a useful proof-of-concept disease model. DESIGN: Investigator initiated, monocentre, nTreg dose escalation, phase I/IIa clinical trial (ONEnTreg13). SETTING: Charité-University Hospital, Berlin, Germany, within the ONE study consortium (funded by the European Union). PARTICIPANTS: Recipients of living donor kidney transplant (ONEnTreg13, n=11) and corresponding reference group trial (ONErgt11-CHA, n=9). INTERVENTIONS: CD4+ CD25+ FoxP3+ nTreg products were given seven days after kidney transplantation as one intravenous dose of 0.5, 1.0, or 2.5-3.0×106 cells/kg body weight, with subsequent stepwise tapering of triple immunosuppression to low dose tacrolimus monotherapy until week 48. MAIN OUTCOME MEASURES: The primary clinical and safety endpoints were assessed by a composite endpoint at week 60 with further three year follow-up. The assessment included incidence of biopsy confirmed acute rejection, assessment of nTreg infusion related adverse effects, and signs of over immunosuppression. Secondary endpoints addressed allograft functions. Accompanying research included a comprehensive exploratory biomarker portfolio. RESULTS: For all patients, nTreg products with sufficient yield, purity, and functionality could be generated from 40-50 mL of peripheral blood taken two weeks before kidney transplantation. None of the three nTreg dose escalation groups had dose limiting toxicity. The nTreg and reference groups had 100% three year allograft survival and similar clinical and safety profiles. Stable monotherapy immunosuppression was achieved in eight of 11 (73%) patients receiving nTregs, while the reference group remained on standard dual or triple drug immunosuppression (P=0.002). Mechanistically, the activation of conventional T cells was reduced and nTregs shifted in vivo from a polyclonal to an oligoclonal T cell receptor repertoire. CONCLUSIONS: The application of autologous nTregs was safe and feasible even in patients who had a kidney transplant and were immunosuppressed. These results warrant further evaluation of Treg efficacy and serve as the basis for the development of next generation nTreg approaches in transplantation and any immunopathologies. TRIAL REGISTRATION: NCT02371434 (ONEnTreg13) and EudraCT:2011-004301-24 (ONErgt11).


Assuntos
Imunossupressão/métodos , Imunossupressores/administração & dosagem , Transplante de Rim/métodos , Linfócitos T Reguladores/transplante , Tacrolimo/administração & dosagem , Adulto , Aloenxertos/imunologia , Estudos de Viabilidade , Feminino , Alemanha , Sobrevivência de Enxerto/imunologia , Humanos , Infusões Intravenosas , Rim/imunologia , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Resultado do Tratamento , Suspensão de Tratamento
4.
Life Sci ; 261: 118487, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32979361

RESUMO

AIMS: Previously we identified four Tocilizumab mimotopes and antibodies induced by these mimotopes could bind to IL-6R (interleukin-6 receptor) and regulate the downstream signaling pathways. On the basis of obtained research data, we sought to investigate whether the therapeutic strategies by Tocilizumab mimotope vaccination could be effective in the renal fibrosis model and show the desired activity by inhibiting IL-6 signaling in current study. MAIN METHODS: We immunized the mice with the Tocilizumab mimotope and then performed the unilateral ureteric obstruction (UUO) surgery. Masson-trichrome staining and immunohistochemistry were performed to evaluate the renal fibrosis. The activations and differentiations of F4/80+ cells in the spleens and kidneys were detected by flow cytometry, immunohistochemistry and immunofluorescence. Signaling pathways involved IL-6, pro-fibrotic and ferroptosis were analyzed by immunoblot assay. The free iron and lipid oxidation end product were performed by Prussian blue staining and immunohistochemistry. The injury and apoptosis in the kidneys were evaluated by immunofluorescence. KEY FINDINGS: The results showed the mimotope vaccination could reduce the level of fibrosis, injury and apoptosis by down-regulating the pro-fibrotic proteins, alleviating the activations and differentiations of macrophage F4/80+ cells in UUO models. IL-6/ERK signaling pathway was inhibited with the mimotope vaccination. The ferroptosis inhibited proteins significantly increased after the mimotope vaccination. On the contrary, the levels of free iron and lipid oxidation end product were observed to decrease in the mimotope treatment group. SIGNIFICANCE: Our results suggested that the Tocilizumab mimotope vaccination might be an alternative therapy to against renal fibrosis.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Ferroptose/efeitos dos fármacos , Interleucina-6/imunologia , Rim/efeitos dos fármacos , Lesão Renal Aguda/imunologia , Lesão Renal Aguda/patologia , Animais , Modelos Animais de Doenças , Feminino , Fibrose , Rim/imunologia , Rim/lesões , Rim/patologia , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos
5.
PLoS One ; 15(9): e0238816, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32898157

RESUMO

Interleukin-10 (IL-10), a cytokine with anti-inflammatory effects, is produced by renal parenchymal cells and bone marrow derived cells. Both endogenous and exogenous IL-10 are protective in cisplatin-induced acute kidney injury. However, the source of endogenous IL-10 in cisplatin-induced nephrotoxicity is not clear. Bone marrow chimera experiments in IL10-KO mice indicated that bone marrow derived cells were the primary source of IL-10 in cisplatin nephrotoxicity. Cell specific deletion of IL-10 in T regulatory cells and dendritic cells was accomplished using Foxp3 and CD11c driven cre recombination in IL10flox/flox mice, respectively. Upon treatment with cisplatin, both the IL10flox/flox and the Foxp3YFP-Cre x IL10flox/flox mice developed similar degrees of kidney injury. However, mice with the dendritic cell deletion of IL-10 showed more severe structural and functional changes in the kidney compared to the IL10flox/flox mice. These results indicate that IL-10 from dendritic cells but not from T regulatory cells offers significant endogenous protection against cisplatin induced nephrotoxicity.


Assuntos
Cisplatino/efeitos adversos , Células Dendríticas/metabolismo , Interleucina-10/metabolismo , Rim/citologia , Rim/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Rim/imunologia , Rim/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
6.
Transplantation ; 104(8): 1591-1603, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732836

RESUMO

BACKGROUND: Combined liver-kidney transplantation (CLKT) improves survival for liver transplant recipients with renal dysfunction; however, the tenuous perioperative hemodynamic and metabolic milieu in high-acuity CLKT recipients increases delayed graft function and kidney allograft failure. We sought to analyze whether delayed KT through pumping would improve kidney outcomes following CLKT. METHODS: A retrospective analysis (University of California Los Angeles [n = 145], Houston Methodist Hospital [n = 79]) was performed in all adults receiving CLKT at 2 high-volume transplant centers from February 2004 to January 2017, and recipients were analyzed for patient and allograft survival as well as renal outcomes following CLKT. RESULTS: A total of 63 patients (28.1%) underwent delayed implantation of pumped kidneys during CLKT (dCLKT) and 161 patients (71.9%) received early implantation of nonpumped kidneys during CLKT (eCLKT). Most recipients were high-acuity with median biologic model of end-stage liver disease (MELD) score of, 35 for dCLKT and 34 for eCLKT (P = ns). Pretransplant, dCLKT had longer intensive care unit stay, were more often intubated, and had greater vasopressor use. Despite this, dCLKT exhibited improved 1-, 3-, and 5-year patient and kidney survival (P = 0.02) and decreased length of stay (P = 0.001), kidney allograft failure (P = 0.012), and dialysis duration (P = 0.031). This reduced kidney allograft futility (death or continued need for hemodialysis within 3 mo posttransplant) for dCLKT (6.3%) compared with eCLKT (19.9%) (P = 0.013). CONCLUSIONS: Delayed implantation of pumped kidneys is associated with improved patient and renal allograft survival and decreased hospital length of stay despite longer kidney cold ischemia. These data should inform the ethical debate as to the futility of performing CLKT in high-acuity recipients.


Assuntos
Doença Hepática Terminal/cirurgia , Rejeição de Enxerto/epidemiologia , Transplante de Rim/efeitos adversos , Transplante de Fígado/efeitos adversos , Preservação de Órgãos/métodos , Idoso , Aloenxertos/imunologia , Aloenxertos/provisão & distribução , Isquemia Fria/instrumentação , Isquemia Fria/métodos , Isquemia Fria/estatística & dados numéricos , Doença Hepática Terminal/complicações , Estudos de Viabilidade , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/imunologia , Humanos , Rim/imunologia , Transplante de Rim/ética , Transplante de Rim/métodos , Transplante de Rim/estatística & dados numéricos , Transplante de Fígado/ética , Transplante de Fígado/métodos , Transplante de Fígado/estatística & dados numéricos , Masculino , Futilidade Médica/ética , Pessoa de Meia-Idade , Preservação de Órgãos/instrumentação , Preservação de Órgãos/estatística & dados numéricos , Perfusão/instrumentação , Perfusão/métodos , Perfusão/estatística & dados numéricos , Insuficiência Renal/etiologia , Insuficiência Renal/cirurgia , Estudos Retrospectivos , Fatores de Tempo , Tempo para o Tratamento/estatística & dados numéricos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/ética , Transplante Homólogo/métodos , Resultado do Tratamento
7.
Transplantation ; 104(8): 1703-1711, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732850

RESUMO

BACKGROUND: There are limited data on the outcome of transplant recipients with familial Mediterranean fever (FMF)-associated AA amyloidosis. The aim of the present study is to evaluate demographic, clinical, laboratory, and prognostic characteristics and outcome measures of these patients. METHODS: Eighty-one renal transplant recipients with FMF-associated AA amyloidosis (group 1) and propensity score-matched transplant recipients (group 2, n = 81) with nonamyloidosis etiologies were evaluated in this retrospective, multicenter study. Recurrence of AA amyloidosis was diagnosed in 21 patients (group 1a), and their features were compared with 21 propensity score-matched recipients with FMF amyloidosis with no laboratory signs of recurrence (group 1b). RESULTS: The risk of overall allograft loss was higher in group 1 compared with group 2 (25 [30.9%] versus 12 [14.8%]; P = 0.015 [hazard ratio, 2.083; 95% confidence interval, 1.126-3.856]). Patients in group 1 were characterized by an increased risk of mortality compared with group 2 (11 [13.6%] versus 0%; P = 0.001 [hazard ratio, 1.136; 95% confidence interval, 1.058-1.207]). Kaplan-Meier analysis revealed that 5- and 10-year patient survival rates in group 1 (92.5% and 70.4%) were significantly lower than in group 2 (100% and 100%; P = 0.026 and P = 0.023, respectively). Although not reaching significance, overall, 5- and 10-year graft survival rates (57.1%, 94.7%, and 53.8%, respectively) in group 1a were worse than in group 1b (76.2%, 95%, and 77.8%, respectively; P = 0.19, P = 0.95, and P = 0.27, respectively). CONCLUSIONS: AA amyloidosis is associated with higher risk of mortality after kidney transplantation. Inflammatory indicators should be monitored closely, and persistent high levels of acute-phase reactants should raise concerns about amyloid recurrence in allograft.


Assuntos
Amiloidose/cirurgia , Febre Familiar do Mediterrâneo/complicações , Rejeição de Enxerto/mortalidade , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Adulto , Aloenxertos/imunologia , Aloenxertos/patologia , Amiloidose/imunologia , Amiloidose/mortalidade , Amiloidose/patologia , Biópsia , Febre Familiar do Mediterrâneo/imunologia , Febre Familiar do Mediterrâneo/mortalidade , Febre Familiar do Mediterrâneo/cirurgia , Feminino , Seguimentos , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto/imunologia , Humanos , Estimativa de Kaplan-Meier , Rim/imunologia , Rim/patologia , Falência Renal Crônica/imunologia , Falência Renal Crônica/mortalidade , Falência Renal Crônica/patologia , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Proteína Amiloide A Sérica/imunologia , Proteína Amiloide A Sérica/metabolismo , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
8.
PLoS One ; 15(8): e0237086, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764782

RESUMO

Paramylon is a novel ß-glucan that is stored by Euglena gracilis Z, which is a unicellular photosynthesizing green alga with characteristics of both animals and plants. Recent studies have indicated that paramylon functions as an immunomodulator or a dietary fiber. Currently, chronic kidney disease (CKD) is a global health problem, and there is no effective preventive treatment for CKD progression. However, paramylon may suppress the progression of CKD via the elimination of uremic toxins or modulation of gut microbiota, leading to the alleviation of inflammation. The aim of this study was to evaluate the effect of paramylon in CKD rat model. Eight-week-old male Wistar rats with a 5/6 nephrectomy were given either a normal diet or a diet containing 5% paramylon for 8 weeks. Proteinuria was measured intermittently. Serum and kidney tissues were harvested after sacrifice. We performed a renal molecular and histopathological investigation, serum metabolome analysis, and gut microbiome analysis. The results showed that paramylon attenuated renal function, glomerulosclerosis, tubulointerstitial injury, and podocyte injury in the CKD rat model. Renal fibrosis, tubulointerstitial inflammatory cell infiltration, and proinflammatory cytokine gene expression levels tended to be suppressed with paramylon treatment. Further, paramylon inhibited the accumulation of uremic toxins, including tricarboxylic acid (TCA) cycle-related metabolites and modulated a part of CKD-related gut microbiota in the CKD rat model. In conclusion, we suggest that paramylon mainly inhibited the absorption of non-microbiota-derived uremic solutes, leading to protect renal injury via anti-inflammatory and anti-fibrotic effects. Paramylon may be a novel compound that can act against CKD progression.


Assuntos
Glucanos/farmacologia , Rim/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Proteinúria/tratamento farmacológico , Insuficiência Renal Crônica/tratamento farmacológico , Administração Oral , Animais , Ciclo do Ácido Cítrico/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Euglena gracilis/química , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Glucanos/isolamento & purificação , Glucanos/uso terapêutico , Humanos , Mediadores da Inflamação/metabolismo , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Rim/imunologia , Rim/patologia , Masculino , Substâncias Protetoras/isolamento & purificação , Substâncias Protetoras/uso terapêutico , Proteinúria/sangue , Proteinúria/patologia , Ratos , Ratos Wistar , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/urina , Toxinas Biológicas/sangue , Toxinas Biológicas/metabolismo
9.
Toxicol Lett ; 333: 130-139, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32763311

RESUMO

Trichloroethylene (TCE) is a widely used industrial solvent that causes trichloroethylene hypersensitivity syndrome (THS) with multi-system damage, including kidney injury. Clinical studies have shown that the complement system is important for TCE-induced kidney injury. Our previous study found excessive deposition of complement C3, mainly on the glomerulus, indicating that local renal complement is activated after TCE sensitisation. However, whether local renal complement activation mediates TCE-induced immune kidney injury and the underlying mechanisms remain unknown. Therefore, we established a TCE percutaneous sensitisation BALB/c mouse model to explore the mechanisms by pretreating with or without the complement activation antagonist, cathepsin L inhibitor (CatLi). As expected, more C3 and C3a were detected mainly on glomerulus of TCE positive sensitisation (TCE+) mice. Renal dysfunction and pathological damage were also clearly observed in TCE+ mice. Moreover, the mRNA and protein expression of ET-1 increased significantly with local renal complement activation after TCE sensitisation, leading to cytokines release and inflammation. In addition, activation of p38MAPK and NF-κBp65 pathways were detected in kidneys of TCE+ mice, and CatLi pretreatment decreased these changes through complement activation antagonisation. Our research uncovered a novel role of local renal complement activation during immune kidney injury after TCE sensitisation through induction of ET-1 signalling and inflammation.


Assuntos
Ativação do Complemento/imunologia , Endotelina-1/metabolismo , Hipersensibilidade/metabolismo , Rim/efeitos dos fármacos , Insuficiência Renal/metabolismo , Tricloroetileno/toxicidade , Animais , Ativação do Complemento/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Hipersensibilidade/imunologia , Inflamação , Rim/imunologia , Rim/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/efeitos dos fármacos , NF-kappa B/imunologia , Insuficiência Renal/induzido quimicamente , Insuficiência Renal/imunologia , Transdução de Sinais
10.
Toxicol Lett ; 333: 97-104, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32763312

RESUMO

Proton pump inhibitors (PPIs) have wide pleiotropic action in addition to their therapeutic potential in gastroesophageal reflux diseases. Conversely, recent reports revealed a significant incidence of toxic events of PPIs including nephritis, osteoporosis, and cardiac damage. Thus, the study was designed to reconcile the deceptive contraindications. The present investigation targeted to reveal the toxic impact of sub-acute and sub-chronic administration of pantoprazole (PPZ) with different concentrations (low dose 4 mg/kg, medium-dose 8 mg/kg and high dose 16 mg/kg once a day) on normal vascular endothelium and renal tissue of rats. Vascular endothelial dysfunction (VED) was estimated by the contractility of an isolated aortic ring, nitrite/nitrate concentration, oxidative stress, and integrity of the endothelium layer. Moreover, the renal abnormalities were further confirmed by an increased level of serum creatinine, blood urea nitrogen (BUN), the incidence of microproteinuria, and structural alteration. Sub-acute administration of PPZ treatment did not produce any toxicological impact on endothelium and renal tissue. Whereas, sub-chronic administration of PPZ treatment causes moderate VED and renal dysfunction in a dose-dependent manner. Sub-chronic treatment of PPZ also influences the mitigation of NO and elevation of oxidative stress. Collecting all the evidence, it concludes that decreased nitric oxide availability and increased levels of oxidative stress may be a possible underlying mechanism of causing VED and renal abnormalities from high-dose PPZ treatment.


Assuntos
Aorta Torácica/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Rim/efeitos dos fármacos , Pantoprazol/toxicidade , Inibidores da Bomba de Prótons/toxicidade , Administração Oral , Animais , Aorta Torácica/imunologia , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Citocinas/sangue , Relação Dose-Resposta a Droga , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Feminino , Rim/imunologia , Rim/metabolismo , Rim/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Nitratos/metabolismo , Nitritos/metabolismo , Ratos , Ratos Wistar , Vasodilatação/efeitos dos fármacos
11.
J Vis Exp ; (160)2020 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-32658202

RESUMO

Tissue-resident memory T cell (TRM) is a rapidly expanding field of immunology research. Isolating T cells from various non-lymphoid tissues is one of the key steps to investigate TRMs. There are slight variations in lymphocyte isolation protocols for different organs. Kidney is an essential non-lymphoid organ with numerous immune cell infiltration especially after pathogen exposure or autoimmune activation. In recent years, multiple labs including our own have started characterizing kidney resident CD8+ T cells in various physiological and pathological settings in both mouse and human. Due to the abundance of T lymphocytes, kidney represents an attractive model organ to study TRMs in non-mucosal or non-barrier tissues. Here, we will describe a protocol commonly used in TRM-focused labs to isolate CD8+ T cells from mouse kidneys following systemic viral infection. Briefly, using an acute lymphocytic choriomeningitis virus (LCMV) infection model in C57BL/6 mice, we demonstrate intravascular CD8+ T cell labeling, enzymatic digestion, and density gradient centrifugation to isolate and enrich lymphocytes from mouse kidneys to make samples ready for the subsequent flow cytometry analysis.


Assuntos
Linfócitos T CD8-Positivos/citologia , Citometria de Fluxo , Rim/citologia , Animais , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Memória Imunológica/imunologia , Rim/imunologia , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/patologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL
12.
Am J Physiol Endocrinol Metab ; 319(1): E217-E231, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32516026

RESUMO

We previously demonstrated that circulating extracellular vesicles (EVs) from patients with valvular heart disease (VHD; vEVs) contain inflammatory components and inhibit endothelium-dependent vasodilation. Neutrophil chemotaxis plays a key role in renal dysfunction, and dexmedetomidine (DEX) can reduce renal dysfunction in cardiac surgery. However, the roles of vEVs in neutrophil chemotaxis and effects of DEX on vEVs are unknown. Here, we investigated the impact of vEVs on neutrophil chemotaxis in kidneys and the influence of DEX on vEVs. Circulating EVs were isolated from healthy subjects and patients with VHD. The effects of EVs on chemokine generation, forkhead box protein O3a (FOXO3a) pathway activation and neutrophil chemotaxis on cultured human umbilical vein endothelial cells (HUVECs) and kidneys in mice and the influence of DEX on EVs were detected. vEVs increased FOXO3a expression, decreased phosphorylation of Akt and FOXO3a, promoted FOXO3a nuclear translocation, and activated the FOXO3a signaling pathway in vitro. DEX pretreatment reduced vEV-induced CXCL4 and CCL5 expression and neutrophil chemotaxis in cultured HUVECs via the FOXO3a signaling pathway. vEVs were also found to suppress Akt phosphorylation and activate FOXO3a signaling to increase plasma levels of CXCL4 and CCL5 and neutrophil accumulation in kidney. The overall mechanism was inhibited in vivo with DEX pretreatment. Our data demonstrated that vEVs induced CXCL4-CCL5 to stimulate neutrophil infiltration in kidney, which can be inhibited by DEX via the FOXO3a signaling. Our findings reveal a unique mechanism involving vEVs in inducing neutrophils chemotaxis and may provide a novel basis for using DEX in reducing renal dysfunction in valvular heart surgery.


Assuntos
Quimiotaxia de Leucócito/imunologia , Vesículas Extracelulares/imunologia , Doenças das Valvas Cardíacas/imunologia , Células Endoteliais da Veia Umbilical Humana/imunologia , Rim/imunologia , Neutrófilos/imunologia , Insuficiência Renal/imunologia , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Adulto , Animais , Estudos de Casos e Controles , Quimiocina CCL5/efeitos dos fármacos , Quimiocina CCL5/imunologia , Quimiocina CCL5/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Dexmedetomidina/farmacologia , Vesículas Extracelulares/efeitos dos fármacos , Vesículas Extracelulares/metabolismo , Feminino , Proteína Forkhead Box O3/efeitos dos fármacos , Proteína Forkhead Box O3/imunologia , Proteína Forkhead Box O3/metabolismo , Doenças das Valvas Cardíacas/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Fosforilação , Fator Plaquetário 4/efeitos dos fármacos , Fator Plaquetário 4/imunologia , Fator Plaquetário 4/metabolismo , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Insuficiência Renal/metabolismo , Vasodilatação
13.
Am J Physiol Renal Physiol ; 318(6): F1441-F1453, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32390512

RESUMO

Carbonic anhydrase II knockout (Car2-/-) mice have depleted numbers of renal intercalated cells, which are increasingly recognized to be innate immune effectors. We compared pyelonephritis susceptibility following reciprocal renal transplantations between Car2-/- and wild-type mice. We examined the effect of pharmacological CA suppression using acetazolamide in an experimental murine model of urinary tract infection. Car2-/- versus wild-type mice were compared for differences in renal innate immunity. In our transplant scheme, mice lacking CA-II in the kidney had increased pyelonephritis risk. Mice treated with acetazolamide had lower kidney bacterial burdens at 6 h postinfection, which appeared to be due to tubular flow from diuresis because comparable results were obtained when furosemide was substituted for acetazolamide. Isolated Car2-/- kidney cells enriched for intercalated cells demonstrated altered intercalated cell innate immune gene expression, notably increased calgizzarin and insulin receptor expression. Intercalated cell number and function along with renal tubular flow are determinants of pyelonephritis risk.


Assuntos
Acetazolamida/farmacologia , Anidrase Carbônica II/deficiência , Inibidores da Anidrase Carbônica/farmacologia , Infecções por Escherichia coli/prevenção & controle , Rim/efeitos dos fármacos , Pielonefrite/prevenção & controle , Infecções Urinárias/prevenção & controle , Acidose/enzimologia , Acidose/genética , Animais , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/genética , Modelos Animais de Doenças , Infecções por Escherichia coli/enzimologia , Infecções por Escherichia coli/genética , Infecções por Escherichia coli/microbiologia , Regulação da Expressão Gênica no Desenvolvimento , Predisposição Genética para Doença , Imunidade Inata , Rim/enzimologia , Rim/imunologia , Rim/microbiologia , Transplante de Rim , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pielonefrite/enzimologia , Pielonefrite/genética , Pielonefrite/microbiologia , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Proteínas S100/genética , Proteínas S100/metabolismo , Infecções Urinárias/enzimologia , Infecções Urinárias/genética , Infecções Urinárias/microbiologia , Escherichia coli Uropatogênica/patogenicidade
14.
Nat Rev Nephrol ; 16(7): 391-407, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32372062

RESUMO

Dendritic cells (DCs) are chief inducers of adaptive immunity and regulate local inflammatory responses across the body. Together with macrophages, the other main type of mononuclear phagocyte, DCs constitute the most abundant component of the intrarenal immune system. This network of functionally specialized immune cells constantly surveys its microenvironment for signs of injury or infection, which trigger the initiation of an immune response. In the healthy kidney, DCs coordinate effective immune responses, for example, by recruiting neutrophils for bacterial clearance in pyelonephritis. The pro-inflammatory actions of DCs can, however, also contribute to tissue damage in various types of acute kidney injury and chronic glomerulonephritis, as DCs recruit and activate effector T cells, which release toxic mediators and maintain tubulointerstitial immune infiltrates. These actions are counterbalanced by DC subsets that promote the activation and maintenance of regulatory T cells to support resolution of the immune response and allow kidney repair. Several studies have investigated the multiple roles for DCs in kidney homeostasis and disease, but it has become clear that current tools and subset markers are not sufficient to accurately distinguish DCs from macrophages. Multidimensional transcriptomic analysis studies promise to improve mononuclear phagocyte classification and provide a clearer view of DC ontogeny and subsets.


Assuntos
Lesão Renal Aguda/imunologia , Células Dendríticas/imunologia , Glomerulonefrite/imunologia , Inflamação/imunologia , Rim/imunologia , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Perfilação da Expressão Gênica , Humanos , Rim/citologia , Ativação Linfocitária/imunologia , Macrófagos/imunologia , Neutrófilos/imunologia , Pielonefrite/imunologia , Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia
16.
Artigo em Chinês | MEDLINE | ID: mdl-32306687

RESUMO

Objective: To explore the possible role of C5a in the pathogenesis of renal injury in TCE- sensitized mice, to analyze the impact of expression of neutrophil gelatinase-associated lipocalin (NGAL) and monocyte chemotactic protein-1 (MCP-1) in the presence or absence of C5a receptor antagonist (C5aRA) pretreatment. Methods: A total of 50 female specific pathogens free(SPF) BALB/c mice were randomly divided into blank control group (n=5) , solvent control group (n=5) , TCE group (n=20) , and TCE+C5aRA group (n= 20) . After one week for adaptive feeding, a mouse model of TCE-induced skin sensitization was established by treating with 50% TCE and 30% TCE in turn. The mice in solvent control group accept same reagents without TCE and the mice in blank control group underwent nothing. In TCE +C5aRA group, except for the TCE solution treatment, mice were intraperitoneally injected with 0.5 mg/kg C5aRA solution at the time of challenge. And the skin erythema and edema reaction were scored 24 h after the last challenge. The mice were divided into sensitization positive group and sensitization negative group according to the scoring result. The mice were aseptically sacrificed 72 h after the last challenge to obtain the kidneys. The structural damage of kidney was observed after histopathological staining. The levels of NGAL and MCP-1 mRNA and proteins were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) , respectively. Results: The sensitization rate of mice in TCE group and TCE+C5aRA group was 45.0% (9/20) and 40.0% (8/20) , respectively. No skin lesions was found in the mice of blank control group and solvent control group. The results of histopathological staining showed that the TCE sensitization positive mice showed renal tubular dilatation, vacuolar degeneration of renal tubular epithelial cells, and infiltration of interstitial cells. The pathological damage of the kidney in TCE sensitization positive group was mild, and no inflammatory cell infiltration was seen. The data of qRT-PCR showed that the expression levels of NGAL and MCP-1 mRNA in the TCE sensitization positive group were significantly increased than in solvent control group and TCE sensitization negative group (P<0.05) , while the levels of NGAL and MCP-1 mRNA in TCE+C5aRA sensitization positive group were decreased than TCE sensitization positive group (P <0.05) . The results of IHC showed that the expression levels of NGAL and MCP-1 in TCE protein sensitization positive group were significantly higher than those in solvent control group and TCE sensitization negative group (P<0.05) . After C5aRA pretreatment, the expression levels of NGAL and MCP-1 protein were decreased than the mice in TCE sensitization positive group (P<0.05) . Conclusion: The regulation of C5a on the expression of MCP-1 and NGAL may participate in TCE- induced mice kidney damage, and pharmacological inhibition of C5a seems to be an effective way to protect the kidney injury in TCE-sensitized mice.


Assuntos
Quimiocina CCL2/imunologia , Complemento C5a/antagonistas & inibidores , Complemento C5a/imunologia , Rim/imunologia , Lipocalina-2/imunologia , Animais , Feminino , Rim/fisiopatologia , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Aleatória , Tricloroetileno
17.
Am J Physiol Renal Physiol ; 318(6): F1327-F1340, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32223310

RESUMO

Asymptomatic hyperuricemia is frequently observed in patients with kidney disease. Although a substantial number of epidemiologic studies have suggested that an elevated uric acid level plays a causative role in the development and progression of kidney disease, whether hyperuricemia is simply a result of decreased renal excretion of uric acid or is a contributor to kidney disease remains a matter of debate. Over the last two decades, multiple experimental studies have expanded the knowledge of the biological effects of uric acid beyond its role in gout. In particular, uric acid induces immune system activation and alters the characteristics of resident kidney cells, such as tubular epithelial cells, endothelial cells, and vascular smooth muscle cells, toward a proinflammatory and profibrotic state. These findings have led to an increased awareness of uric acid as a potential and modifiable risk factor in kidney disease. Here, we discuss the effects of uric acid on the immune system and subsequently review the effects of uric acid on the kidneys mainly in the context of inflammation.


Assuntos
Hiperuricemia/sangue , Rim/metabolismo , Nefrite/sangue , Ácido Úrico/sangue , Animais , Biomarcadores/sangue , Humanos , Hiperuricemia/epidemiologia , Hiperuricemia/imunologia , Rim/imunologia , Rim/fisiopatologia , Nefrite/epidemiologia , Nefrite/imunologia , Nefrite/fisiopatologia , Medição de Risco , Fatores de Risco , Transdução de Sinais
18.
PLoS Pathog ; 16(4): e1008443, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32343740

RESUMO

Staphylococcus aureus (SA) is the causative agent of both skin/soft tissue infections as well as invasive bloodstream infections. Though vaccines have been developed to target both humoral and T cell-mediated immune responses against SA, they have largely failed due to lack of protective efficacy. Group 1 CD1-restricted T cells recognize lipid rather than peptide antigens. Previously found to recognize lipids derived from cell wall of Mycobacterium tuberculosis (Mtb), these cells were associated with protection against Mtb infection in humans. Using a transgenic mouse model expressing human group 1 CD1 molecules (hCD1Tg), we demonstrate that group 1 CD1-restricted T cells can recognize SA-derived lipids in both immunization and infection settings. Systemic infection of hCD1Tg mice showed that SA-specific group 1 CD1-restricted T cell response peaked at 10 days post-infection, and hCD1Tg mice displayed significantly decreased kidney pathology at this time point compared with WT control mice. Immunodominant SA lipid antigens recognized by group 1 CD1-restricted T cells were comprised mainly of cardiolipin and phosphatidyl glycerol, with little contribution from lysyl-phosphatidyl glycerol which is a unique bacterial lipid not present in mammals. Group 1 CD1-restricted T cell lines specific for SA lipids also conferred protection against SA infection in the kidney after adoptive transfer. They were further able to effectively control SA replication in vitro through direct antigen presentation by group 1 CD1-expressing BMDCs. Together, our data demonstrate a previously unknown role for group 1 CD1-restricted SA lipid-specific T cells in the control of systemic MRSA infection.


Assuntos
Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Linfócitos T/imunologia , Animais , Antígenos CD1/genética , Antígenos CD1/imunologia , Humanos , Imunização , Rim/imunologia , Rim/microbiologia , Lipídeos/imunologia , Camundongos , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/fisiologia
19.
Transplant Proc ; 52(3): 857-864, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32143865

RESUMO

Monoclonal gammopathy of renal significance (MGRS) is a new concept with evolving evidence for treatment. MGRS in the transplant kidney is a rare cause of renal transplant dysfunction that can lead to graft loss. Most cases of post-transplant MGRS are due to recurrent disease. Clone-specific chemotherapy is required to target the underlying clone, and this may improve graft survival; however, this can be challenging, as most patients are elderly with age-related comorbidities and may have complications associated with increasing immunosuppression. Here, we report 3 cases of renal allograft MGRS, and each case highlights different challenges in the diagnosis and management of this condition.


Assuntos
Nefropatias/etiologia , Transplante de Rim/efeitos adversos , Paraproteinemias/etiologia , Complicações Pós-Operatórias/etiologia , Idoso , Feminino , Humanos , Rim/imunologia , Nefropatias/imunologia , Masculino , Pessoa de Meia-Idade , Paraproteinemias/imunologia , Complicações Pós-Operatórias/imunologia
20.
PLoS One ; 15(2): e0228096, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32023273

RESUMO

BACKGROUND: The hypothesis was tested that parameters of an aged T-cell compartment associate with the risk for late rejection after kidney transplantation. METHODS: Recipients of a kidney transplant in the period 2007-2013 were (N = 365) were included. T cells were characterized prior to transplantation by flow cytometry as naive (CD45RO-CCR7+), central-memory (CD45RO+CCR7+), effector-memory (CD45RO-CCR7-) or terminally differentiated CD8+ Temra (CD45RO-/CCR7-/CD28-) cells. T cell telomere length and thymic output were assessed prior to transplantation in 202 recipients. Follow-up was until December 2018. The date of the first time of biopsy-proven late rejection (>6 months after transplantation) was used to calculate the rejection-free survival time. RESULTS: Fifty cases of biopsy-proven rejection were recorded. Thymic output and T cell telomere length did not associate with late rejection-free survival. However, the percentage and absolute numbers of CD8+Temra and CD28null CD8+ T cells were significantly lower in patients with late rejection. Specifically, in the highest tertile of percentages of CD28null CD8+ T cells, the cumulative incidence of late rejection at 5 and 10 years was only 5% and 8% compared to 16% and 20% in the middle to lowest tertile (p = 0.002). Multivariate proportional hazard analysis showed that percentage and absolute number of CD28null CD8+ T cells remained significantly associated with late rejection and rejection-related graft loss. CONCLUSION: High numbers of differentiated CD28null CD8+ T cells decrease the risk for late rejection and rejection-related graft loss after kidney transplantation.


Assuntos
Antígenos CD28/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Rejeição de Enxerto/patologia , Transplante de Rim , Adolescente , Adulto , Idoso , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Feminino , Seguimentos , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/mortalidade , Humanos , Estimativa de Kaplan-Meier , Rim/imunologia , Rim/patologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Risco , Transplante Homólogo , Adulto Jovem
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