RESUMO
Renal ischemia-reperfusion injury (IRI) is an integral process in renal transplantation, which results in compromised graft survival. Macrophages play an important role in both the early inflammatory period and late fibrotic period in response to IRI. In this study, we investigated whether scutellarin (SCU) could protect against renal IRI by regulating macrophage polarization. Mice were given SCU (5-50 mg/kg) by gavage 1 h earlier, followed by a unilateral renal IRI. Renal function and pathological injury were assessed 24 h after reperfusion. The results showed that administration of 50 mg/kg SCU significantly improved renal function and renal pathology in IRI mice. In addition, SCU alleviated IRI-induced apoptosis. Meanwhile, it reduced macrophage infiltration and inhibited pro-inflammatory macrophage polarization. Moreover, in RAW 264.7 cells and primary bone marrow-derived macrophages (BMDMs) exposed to SCU, we found that 150 µM SCU inhibited these cells to polarize to an inflammatory phenotype induced by lipopolysaccharide (LPS) and interferon-γ (IFN-γ). However, SCU has no influence on anti-inflammatory macrophage polarization in vivo and in vitro induced by in interleukin-4 (IL-4). Finally, we explored the effect of SCU on the activation of the mitogen-activated protein kinase (MAPK) pathway both in vivo and in vitro. We found that SCU suppressed the activation of the MAPK pathway, including the extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK), and p38. Our results demonstrated that SCU protects the kidney against IRI by inhibiting macrophage infiltration and polarization toward pro-inflammatory phenotype via the MAPK pathway, suggesting that SCU may be therapeutically important in treatment of IRI.
Assuntos
Apigenina , Glucuronatos , Sistema de Sinalização das MAP Quinases , Macrófagos , Traumatismo por Reperfusão , Animais , Masculino , Camundongos , Apigenina/farmacologia , Apoptose/efeitos dos fármacos , Glucuronatos/farmacologia , Glucuronatos/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/prevenção & controle , Inflamação/patologia , Rim/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismoRESUMO
BACKGROUND: Delayed graft function (DGF) is an important complication after kidney transplantation surgery. The present study aimed to develop and validate a nomogram for preoperative prediction of DGF on the basis of clinical and histological risk factors. METHODS: The prediction model was constructed in a development cohort comprising 492 kidney transplant recipients from May 2018 to December 2019. Data regarding donor and recipient characteristics, pre-transplantation biopsy results, and machine perfusion parameters were collected, and univariate analysis was performed. The least absolute shrinkage and selection operator regression model was used for variable selection. The prediction model was developed by multivariate logistic regression analysis and presented as a nomogram. An external validation cohort comprising 105 transplantation cases from January 2020 to April 2020 was included in the analysis. RESULTS: 266 donors were included in the development cohort, 458 kidneys (93.1%) were preserved by hypothermic machine perfusion (HMP), 96 (19.51%) of 492 recipients developed DGF. Twenty-eight variables measured before transplantation surgery were included in the LASSO regression model. The nomogram consisted of 12 variables from donor characteristics, pre-transplantation biopsy results and machine perfusion parameters. Internal and external validation showed good discrimination and calibration of the nomogram, with Area Under Curve (AUC) 0.83 (95%CI, 0.78-0.88) and 0.87 (95%CI, 0.80-0.94). Decision curve analysis demonstrated that the nomogram was clinically useful. CONCLUSION: A DGF predicting nomogram was developed that incorporated donor characteristics, pre-transplantation biopsy results, and machine perfusion parameters. This nomogram can be conveniently used for preoperative individualized prediction of DGF in kidney transplant recipients.
Assuntos
Transplante de Rim , Humanos , Transplante de Rim/efeitos adversos , Função Retardada do Enxerto , Nomogramas , Sobrevivência de Enxerto , Rim , Doadores de Tecidos , Biópsia/efeitos adversos , Fatores de RiscoRESUMO
BACKGROUND: Donor-specific human leukocyte antigen (HLA) class II antibodies (HLA-II Abs) combined with allogeneic endothelial cells (ECs) mediate high-risk rejection in kidney transplant patients. Macrophage accumulation is a significant histological feature of antibody-mediated rejection (AMR) in kidney transplant patients. Here, we further investigated the effect of HLA-II Abs on macrophage phenotypes to provide theoretical basis for clinical treatment of AMR. METHODS: We prepared an experimental model containing HLA-II Ab-stimulated microvascular ECs and peripheral blood mononuclear cells (PBMCs) co-culture and explored the potential relationship of HLA-II Ab, ECs activation, and macrophage differentiation. Immune phenotype of macrophage subsets was analyzed and quantified by flow cytometry. HLA-II Ab activation of ECs induces M2 macrophage differentiation signal pathways which were investigated by qPCR and western blotting. RESULTS: The stimulation of ECs by F(ab')2 fragment of HLA-II Abs led to phosphorylation of PI3K, Akt, and mTOR, which mediated IL-10, ICAM-1, VCAM-1 secretion. The enhanced ICAM-1 and IL-10 promoted the migration of PBMCs and their differentiation into CD68+ and CD163+ (M2-type) macrophages, respectively, but not CD86+ macrophages. CONCLUSION: These findings revealed the PI3K/Akt/mTOR signal pathways activated by HLA-II Abs in ECs and the immune regulation ability of HLA-II Abs to induce PBMC differentiation.
Assuntos
Células Endoteliais , Leucócitos Mononucleares , Humanos , Células Endoteliais/metabolismo , Interleucina-10/metabolismo , Interleucina-10/farmacologia , Molécula 1 de Adesão Intercelular/metabolismo , Molécula 1 de Adesão Intercelular/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/farmacologia , Antígenos HLA , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/farmacologia , Macrófagos , Diferenciação Celular , Rejeição de EnxertoRESUMO
BACKGROUND: Recently, early graft loss has become very rare in living-related kidney transplantation (LKT) as a result of decreased risk of hyperacute rejection and improvements in immunosuppressive regimens. Post-transplant acute thrombotic microangiopathy (TMA) is a rare, multi-factorial disease that often occurs shortly after kidney transplantation and is usually resistant to treatment with dismal renal outcomes. The complement genetic variants may accelerate the development of TMA. However, the complement genetic test was seldom performed in unknown native kidney disease recipients scheduled for LKT. CASE PRESENTATION: We reported three cases of unknown native kidney diseases who had fulminant TMA in the allograft shortly after LKT. Both the donors and the recipients were noted to carry complement genetic variants, which were identified by genetic testing after transplantation. However, all recipients were refractory to treatment and had allograft loss within 3 months after LKT. CONCLUSION: This case series highlights the suggestion to screen complement gene variants in both the donors and the recipients with unknown native kidney diseases scheduled for LKT.
Assuntos
Transplante de Rim , Microangiopatias Trombóticas , Humanos , Imunossupressores , Transplante de Rim/efeitos adversos , Microangiopatias Trombóticas/genética , Doadores de Tecidos , Transplante HomólogoRESUMO
Fibrosis is a pathological feature of chronic kidney disease and its progression correlates with declining renal function. Kidney fibrosis is driven by multiple profibrotic factors. This project examined the regulatory function of WNT1-inducible-signaling pathway protein 1 (WISP1) in the development of kidney fibrosis. Induction of WISP1 by transforming growth factor beta 1 (TGF-ß1), and the role of WISP1 in TGF-ß1/Smad signaling and fibrotic responses, was examined in multiple kidney cells. Kidney expression of WISP1 was examined in mouse models of unilateral ureter obstruction (UUO) and streptozotocin-induced diabetic nephropathy. WISP1 antibody was administered to UUO mice during the induction of kidney injury and the impact on kidney fibrosis was examined. WISP1 expression was upregulated in both mouse models. TGF-ß1-induced expression of WISP1 and profibrotic genes in cultured kidney cells via TGF-ßR1. Recombinant WISP1-induced expression of TGF-ßR1 in kidney cells. Suppression of WISP1 by shRNA or neutralizing antibody reduced TGF-ß1-mediated activation of Smad3, fibrotic gene expression, and fibroblast proliferation. Treatment with WISP1 antibody inhibited the development of kidney fibrosis in UUO mice. WISP1 mediates the profibrotic effects of TGF-ß1 in kidney cells and in kidney disease. Pharmacological blockade of WISP1 exhibits potential as a novel therapy for inhibiting kidney fibrosis.
Assuntos
Proteínas de Sinalização Intercelular CCN/metabolismo , Nefropatias Diabéticas/metabolismo , Fibroblastos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Proteínas de Sinalização Intercelular CCN/genética , Linhagem Celular , Proliferação de Células , Células Cultivadas , Nefropatias Diabéticas/patologia , Fibroblastos/fisiologia , Fibrose , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas/genética , Ratos , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
Acute kidney injury (AKI) refers to a clinical syndrome that occurs as a result of a rapid decline in renal function caused by multiple factors. Renal ischemia/reperfusion (I/R) injury is one of the main causes of AKI and has a high incidence and mortality. However, the specific pathogenesis of renal I/R injury is still unclear. In recent years, a major breakthrough has been made in the study of endoplasmic reticulum stress (ERS)-mediated apoptosis in I/R injury. It has been reported that miRNAs play protective roles in ischemic/reperfused organs, but the molecular mechanisms have not been investigated deeply. In this study, the renal I/R mouse model was used to explore the roles of miR-124 in ERS and in renal I/R injury. The western blot results showed that the expression levels of ERS-related proteins IRE-1α, XBP-1, and glucose-regulated protein 78 (GRP78) were significantly increased in the I/R model group when compared with those in the control group. Meanwhile, qPCR results showed that miR-124 expression was decreased in the I/R injury model, and overexpression of miR-124 using miR-124 mimics effectively reduced the expression of ERS-related proteins and alleviated renal I/R injury. In addition, luciferase reporter assay was performed, and the results showed that IRE-1α and miR-124 may have direct interaction. In conclusion, our data indicated that miR-124 was a negative regulator of ERS via binding to IRE-1α, ultimately conferring its protective effect on the kidney, which demonstrates the regulatory mechanism of miR-124 in renal I/R injury and provides new ideas and methods for the prevention and treatment of renal I/R injury.
Assuntos
Estresse do Retículo Endoplasmático , Endorribonucleases/metabolismo , MicroRNAs/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Traumatismo por Reperfusão/patologia , Injúria Renal Aguda/patologia , Animais , Apoptose , Adesão Celular , Chaperona BiP do Retículo Endoplasmático , Células Epiteliais/patologia , Túbulos Renais/patologia , Camundongos , Ligação Proteica , Traumatismo por Reperfusão/etiologiaRESUMO
Cordycepin (3'-deoxyadenosine) is a naturally occurring adenosine analog and one of the bioactive constituents isolated from Cordyceps sinensis, species of the fungal genus Cordyceps. It has traditionally been a prized Chinese folk medicine for the human well-being. However, the actions of cordycepin against renal ischemia/reperfusion injury (I/R) are still unknown. In the present study, rats were subject to I/R and cordycepin was intragastrically administered for seven consecutive days before surgery to investigate the effects and mechanisms of cordycepin against renal I/R injury. The test results of kidney and peripheral blood samples of experimental animals showed that cordycepin significantly decreased serum blood urea nitrogen and creatinine levels and markedly attenuated cell injury. Mechanistic studies showed that cordycepin significantly regulated inflammation, apoptosis, and oxidative stress. These data provide new insights for investigating the natural product with the nephroprotective effect against I/R, which should be developed as a new therapeutic agent for the treatment of I/R in the future.
Assuntos
Desoxiadenosinas/farmacologia , Nefropatias/patologia , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Humanos , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Nefropatias/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , RatosRESUMO
Background: Due to the current high demand for transplant tissue, an increasing proportion of kidney donors are considered extended criteria donors, which results in a higher incidence of delayed graft function (DGF) in organ recipients. Therefore, it is important to fully investigate the risk factors of DGF, and establish a prediction system to assess donor kidney quality before transplantation.Methods: A total of 333 donation after cardiac death kidney transplant recipients were included in this retrospective study. Both univariate and multivariate analyses were used to analyze the risk factors of DGF occurrence. Receiver operating characteristic (ROC) curves were used to analyze the predictive value of variables on DGF posttransplant.Results: The donor clinical scores, kidney histopathologic Remuzzi scores and hypothermic mechanical perfusion (HMP) parameters (flow and resistance index) were all correlated. 46 recipients developed DGF postoperatively, with an incidence of 13.8% (46/333). Multivariate logistic regression analysis of the kidney transplants revealed that the independent risk factors of DGF occurrence post-transplantation included donor score (OR = 1.12, 95% CI 1.06-1.19, p < 0.001), Remuzzi score (OR = 1.21, 95% CI 1.02-1.43, p = 0.029) and acute tubular injury (ATI) score (OR = 4.72, 95% CI 2.32-9.60, p < 0.001). Prediction of DGF with ROC curve showed that the area under the curve was increased to 0.89 when all variables (donor score, Remuzzi score, ATI score and HMP resistance index) were considered together.Conclusions: Combination of donor clinical information, kidney pre-implant histopathology and HMP parameters provide a more accurate prediction of DGF occurrence post-transplantation than any of the measures alone.
Assuntos
Função Retardada do Enxerto/fisiopatologia , Hipotermia Induzida/métodos , Rim/fisiopatologia , Preservação de Órgãos/métodos , Perfusão/métodos , Adulto , Biópsia , Feminino , Sobrevivência de Enxerto , Humanos , Transplante de Rim , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Preservação de Órgãos/efeitos adversos , Valor Preditivo dos Testes , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Doadores de Tecidos/estatística & dados numéricos , Obtenção de Tecidos e Órgãos/métodosRESUMO
After renal ischemic reperfusion injury, a series of pathological changes, such as impaired intestinal barrier function, intestinal flora, and endotoxin translocation, are caused by intestinal ischemia and hypoxia, which then trigger systemic inflammatory responses and affect the condition and prognosis of the patients. In this study, a rat model of ischemia-reperfusion injury was established by examining changes in renal function, intestinal barrier function, inflammatory index, oxidative stress, and macrophage phenotypes to evaluate the effect of probiotic VSL#3 on renal ischemia-reperfusion injury. The results showed that, after VSL#3 intervention, the levels of BUN, Scr, Cys C, PRO, and NGAL were all significantly decreased compared with the I/R group, while the value of Ccr showed a significant increase. In addition, the concentrations of MPO, IL-1ß, TNF-α, IL-6, ED-1, and PCNA were all significantly lower than those in the I/R group, while the levels of endotoxin, DOA, and D-lactic acid were significantly decreased. Furthermore, the proteins associated with intestinal barrier functions, such as ZO-1, Occludin, and Claudin-1, were significantly upregulated compared with the I/R group. Overall, the VSL#3 intervention group was able to maintain the required number of beneficial intestinal flora and to inhibit the proliferation of harmful bacteria. At the same time, the VSL#3 intervention could also prevent the decrease in the levels of CAT, GSH-PX, H2O2, and T-SOD, while downregulating the expression of Keap1 and Nrf2. After the intervention with the VSL#3, the expression levels of CD68 and CD86 proteins were significantly decreased, while the expression levels of CD163 and CD206 proteins were significantly higher. Further experiments confirmed that the expression of iNOS protein was significantly decreased after the VSL#3 intervention, and the expression of Arg-1 and Ym1 proteins was significantly increased. The VSL#3 was able to induce high expressions of p-GSK-3ß and p-PTEN proteins, while the use of IL-10 antibody impaired the effect of the VSL#3. In summary, this research confirms that probiotics can alleviate renal dysfunction caused by ischemia and reperfusion by protecting the intestinal barrier function and maintaining the functions of intestinal flora. The pathway screening test of this study suggests that IL-10/GSK3ß/PTEN may play an important role in the process of the prototypic VSL#3 inducing M2 transformation of macrophages.
Assuntos
Rim/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Probióticos/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Regulação para Baixo/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Interleucina-10/metabolismo , Rim/metabolismo , Masculino , PTEN Fosfo-Hidrolase/metabolismo , Fenótipo , Ratos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND/AIMS: The association between ACYP2(Acylphosphatase 2) polymorphisms and immunoglobulin A nephropathy (IgAN) risk in the Chinese Han population remains unclear. We aimed to evaluate the association between ACYP2 polymorphisms and IgAN risk by performing a case-control study. METHODS: Eleven ACYP2 single nucleotide polymorphisms (SNPs) from 416 IgAN patients and 495 healthy controls were genotyped using the Sequenom MassARRAY platform. Odds ratio (OR) and 95% confidence interval (CI) were calculated to evaluate the association of ACYP2 polymorphisms with IgAN risk. RESULTS: We observed that rs843720 was significantly associated with an increased risk of IgAN (allele G: OR = 1.23, 95% CI: 1.01-1.49, p = 0.036; dominant model: OR = 1.55, 95% CI: 1.01-2.37, p =0.044; log-additive model: OR = 1.43, 95% CI: 1.04-1.95, p = 0.026) before Bonferroni correction. The SNP rs12615793 was also significantly associated with an increased IgAN risk in the recessive model (OR = 3.33, 95% CI: 1.05-10.51, p = 0.042) before Bonferroni correction. CONCLUSION: These findings suggested that polymorphisms (rs843720 and rs12615793) of ACYP2 may be pivotal in the development of IgAN. However, more functional and association studies with larger sample sizes should be performed to further validate our results in the future.
Assuntos
Hidrolases Anidrido Ácido/genética , Glomerulonefrite por IGA/genética , Polimorfismo de Nucleotídeo Único , Adulto , Povo Asiático , Estudos de Casos e Controles , Intervalos de Confiança , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de ChancesRESUMO
BACKGROUND: Delayed graft function (DGF) is an important complication of kidney transplantation and can be diagnosed according to different definitions. DGF has been suggested to be associated with the long-term outcome of kidney transplantation surgery. However, the best DGF definition for predicting renal transplant outcomes in Chinese donations after cardiac death (DCDs) remains to be determined. METHOD: A total of 372 DCD kidney transplant recipients from June 2013 to July 2017 in the First Affiliated Hospital of Xi'an Jiaotong University were included in this retrospective study to compare 6 different DGF definitions. The relationships of the DGF definitions with transplant outcome were analyzed, including graft loss (GL) and death-censored graft loss (death-censored GL). Renal function indicators, including one-year estimated glomerular filtration rate (eGFR) and three-year eGFR, and were compared between different DGF groups. RESULTS: The incidence of DGF varied from 4.19 to 35.22% according to the different DGF diagnoses. All DGF definitions were significantly associated with three-year GL as well as death-censored GL. DGF based on requirement of hemodialysis within the first week had the best predictive value for GL (AUC 0.77), and DGF based on sCr variation during the first 3 days post-transplant had the best predictive value for three-year death-censored GL (AUC 0.79). Combination of the 48-h sCr reduction ratio and classical DGF can improve the AUC for GL (AUC 0.85) as well as the predictive accuracy for death-censored GL (83.3%). CONCLUSION: DGF was an independent risk factor for poor transplant outcome. The combination of need for hemodialysis within the first week and the 48-h serum creatinine reduction rate has a better predictive value for patient and poor graft outcome.
Assuntos
Função Retardada do Enxerto/diagnóstico , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias/diagnóstico , Doadores de Tecidos , Adulto , Área Sob a Curva , China , Creatinina/sangue , Função Retardada do Enxerto/epidemiologia , Feminino , Taxa de Filtração Glomerular , Sobrevivência de Enxerto , Parada Cardíaca , Humanos , Terapia de Imunossupressão/métodos , Imunossupressores/uso terapêutico , Incidência , Estimativa de Kaplan-Meier , Rim/fisiologia , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Sensibilidade e Especificidade , Fatores de Tempo , Resultado do TratamentoRESUMO
Colorectal neoplasia differentially expressed (CRNDE) served as an oncogenic long noncoding RNA (lncRNA) to be involved in the initialization and development of human cancers. However, the clinical significance and biological function of CRNDE in clear cell renal cell carcinoma (ccRCC) was not fully understood. In our study, we found CRNDE levels were increased in ccRCC tissue specimens and cell lines, and corrected with advanced clinical stage, large tumor size, lymph node metastasis, distant metastasis, and poor pathological grade in patients with ccRCC. Furthermore, levels of CRNDE were negatively correlated with overall survival of patients with ccRCC, and high-expression of CRNDE was an independent poor prognostic factor for patients with ccRCC. Moreover, loss-of-function and gain-of-function approaches showed CRNDE-enhanced ccRCC cell migration and invasion through modulating EMT-associated genes. In conclusion, CRNDE acts as an oncogenic lncRNA in ccRCC.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Prognóstico , RNA Longo não Codificante/genética , Idoso , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Transdução de SinaisRESUMO
BACKGROUND/AIMS: Diabetic nephropathy (DN) is a microangiopathic disease characterized by excessive urinary albumin excretion, which occurs in 30% of patients with diabetes mellitus. It is the second leading cause of end-stage renal diseases in China. Nuclear factor-kappa B (NF-κB) is reported to be closely correlated with the inflammation underlying diabetes-associated renal damage. Crocin, a plant-derived compound, has antioxidant properties that may inhibit NF-κB. METHODS: In the present study, we used a conditionally immortalized mouse podocyte cell line to explore whether crocin could effectively block albuminuria. Cells were incubated with 15 or 25 mM D-glucose to mimic diabetic conditions. The expression of Wilms tumor 1 (WT-1) and synaptopodin was evaluated to identify differentiated podocytes, and the expression of nephrin, podocin, and CD2ap was measured as markers of slit diaphragms, the main structures within the glomerular filtration barrier. RESULTS: The high-glucose conditions led to reduced nephrin, podocin, and CD2ap expression, which was prevented by pretreatment with crocin. The oxidative stress and pro-inflammatory response of podocytes associated with DN induced by high glucose were also reduced by crocin pretreatment. Phosphorylated IκBα (p-IκBα) expression induced by high glucose was also significantly decreased by crocin pretreatment. Moreover, pyrrolidine dithiocarbamate, a NF-κB inhibitor, pyrrolidine dithio carbamate, augmented the protective effects of crocin. CONCLUSION: Our results demonstrate a protective role of crocin against damage to podocytes and slit diaphragms under high-glucose conditions via inhibition of NF-κB. This study presents a potential therapy for DN and contributes to the understanding of the mechanism underlying DN.
Assuntos
Antioxidantes/farmacologia , Carotenoides/farmacologia , Glucose/antagonistas & inibidores , NF-kappa B/genética , Podócitos/efeitos dos fármacos , Pirrolidinas/farmacologia , Tiocarbamatos/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linhagem Celular Transformada , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Combinação de Medicamentos , Sinergismo Farmacológico , Regulação da Expressão Gênica , Glucose/toxicidade , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Estresse Oxidativo , Podócitos/citologia , Podócitos/metabolismo , Transdução de Sinais , Proteínas WT1/genética , Proteínas WT1/metabolismoRESUMO
BACKGROUND: The cases of donation after brain death followed by circulatory death (DBCD) and donation after cardiac death (DCD) have been increased year by year in China. Further research is needed to understand in the outcomes and risk factors of delayed graft function (DGF) in order to minimize the risk of DGF and ameliorate its potential impact on long-term outcomes. This study was to explore the differences in outcomes between DBCD and DCD transplant and the main risk factors for DGF in DBCD. METHODS: Retrospective analysis of the clinical data of 367donations after citizens' death kidney transplant procedures (donors and recipients) between July 2012 and August 2015 at our center. RESULTS: During the study period, the donation success rate was 25.3%. 164 cases of DBCD and 35 cases of DCD had been implemented and 367 kidneys were transplanted. The incidence of DGF in DBCD group were significantly lower than that of DCD group (12.0% vs. 27.0%, p = 0.002). The 1-year percent freedom from acute rejection (AR) was significantly higher in DBCD group compared with it of DCD group (94% vs. 82%, p = 0.036). Multivariate logistic regression analysis of the kidney transplants revealed that the high risk factors for DGF after renal transplantation in DBCD were history of hypertension (Odds Ratio [OR] = 5.88, 95% CI: 1.90 to 18.2, p = 0.002), low blood pressure (BP < 80 mmHg) (OR = 4.86, 95% CI: 1.58 to 14.9, p = 0.006) and serum creatinine of donor (OR = 1.09, 95% CI: 1.03 to 1.16, p = 0.003) before donation. CONCLUSIONS: The outcomes of DBCD could be better than DCD in DGF and AR. The main risk factors for DGF in DBCD kidney transplants are donors with a history of hypertension, low blood pressure, and serum creatinine of donor before donation.
Assuntos
Morte , Transplante de Rim , Avaliação de Resultados em Cuidados de Saúde , Obtenção de Tecidos e Órgãos , Adulto , Morte Encefálica , China , Função Retardada do Enxerto , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: The aim of the present study is to investigate the impact of de novo donor-specific antibodies (dnDSA) on early graft function, to provide objective reference for early clinical diagnosis and reasonable individualized treatment. METHODS: 305 cases of renal transplant patients for the first time were observed in this study. Follow-up time for all recipients was 6 months after operation. HLA antibody, DSA, renal function were monitored after transplant. RESULTS: In total of 305 cases, 66 cases (21.64%) were HLA antibody positive and 21 cases (6.89%) showed acute rejection (AR) in 6 months after transplant. The HLA antibody-positive patients included six cases of dnDSA-positive and 60 cases of dnDSA-negative. The incidence of AR was 2.09% (5/239) in HLA antibody-negative patients, 18.33% (11/60) in HLA antibody positive with DSA-negative patients, and 83.33% (5/6) in HLA antibody-positive patients with DSA-positive. There was a big difference between DSA-negative and DSA-positive patients (p < 0.01). The recovery time of AR patients with DSA-positive were longer than DSA-negative patients, and the recovery graft function of AR patient with DSA-positive were not as good as those with DSA-negative. CONCLUSIONS: The appearance of dnDSA in the early stage of kidney transplantation is a warning sign of AR occurrence. Dynamic monitoring of HLA antibody and DSA could predict the state of graft function, and play an important role in the prevention of AR, timely and effectively.
Assuntos
Rejeição de Enxerto , Antígenos HLA/imunologia , Isoanticorpos/sangue , Transplante de Rim/efeitos adversos , Recuperação de Função Fisiológica/imunologia , Adulto , China , Função Retardada do Enxerto/imunologia , Feminino , Seguimentos , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Rejeição de Enxerto/prevenção & controle , Humanos , Falência Renal Crônica/cirurgia , Testes de Função Renal/métodos , Transplante de Rim/métodos , Masculino , Monitorização Imunológica/métodos , PrognósticoRESUMO
Background and aims: Obesity and insulin resistance are well-known important risk factors for hypertension. This study aimed to investigate the mediating effect of the triglyceride-glucose index (TyG) in the association between Chinese visceral obesity index (CVAI) and hypertension among Chinese middle-aged and older adults. Methods: A total of 10,322 participants aged 45 years and older from CHARLS (2011-2018) were included. Baseline data were collected in 2011 and hypertension incidence data were gathered during follow-up in 2013, 2015 and 2018. Multivariate logistic regression models were constructed to investigate the association of CVAI and TyG with the incidence of hypertension. Additionally, mediation analyses were conducted to evaluate the mediating role of the TyG index in the relationship between CVAI and hypertension. Subgroup analysis was also performed. Results: A total of 2,802 participants developed hypertension during the follow-up period. CVAI and TyG index were independently and significantly associated with hypertension incidence. Increasing quartiles of CVAI and TyG index were associated with high hypertension incidence in middle-aged and older adults. The TyG index was identified as a mediator in the relationship between CVAI and hypertension incidence, with a mediation effect (95% confidence interval) was 12.38% (6.75, 31.81%). Conclusion: Our study found that CVAI and TyG were independently associated with hypertension incidence. TyG played a partial mediating effect in the positive association between CVAI and hypertension incidence.
Assuntos
Hipertensão , Resistência à Insulina , Pessoa de Meia-Idade , Humanos , Idoso , Incidência , Estudos Longitudinais , Aposentadoria , Obesidade/epidemiologia , China/epidemiologia , Glucose , Hipertensão/epidemiologia , TriglicerídeosRESUMO
INTRODUCTION: Both innate and adaptive immune system undergo evolution from low to high vertebrates. Due to the limitation of conventional approaches in identifying broader spectrum of immune cells and molecules from various vertebrates, it remains unclear how immune molecules evolve among vertebrates. OBJECTIVES: Here, we utilized carry out comparative transcriptome analysis in various immune cells across seven vertebrate species. METHODS: Single-cell RNA sequencing (scRNA-seq). RESULTS: We uncovered both conserved and species-specific profiling of gene expression in innate and adaptive immunity. Macrophages exhibited highly-diversified genes and developed sophisticated molecular signaling networks along with evolution, indicating effective and versatile functions in higher species. In contrast, B cells conservatively evolved with less differentially-expressed genes in analyzed species. Interestingly, T cells represented a dominant immune cell populations in all species and unique T cell populations were identified in zebrafish and pig. We also revealed compensatory TCR cascade components utilized by different species. Inter-species comparison of core gene programs demonstrated mouse species has the highest similarity in immune transcriptomes to human. CONCLUSIONS: Therefore, our comparative study reveals gene transcription characteristics across multiple vertebrate species during the evolution of immune system, providing insights for species-specific immunity as well as the translation of animal studies to human physiology and disease.
Assuntos
Imunidade Adaptativa , Imunidade Inata , Transcriptoma , Animais , Humanos , Camundongos , Imunidade Adaptativa/genética , Macrófagos , Suínos , Peixe-Zebra/genética , Imunidade Inata/genéticaRESUMO
Tumor necrosis factor-a--induced protein 8-like 2 (TIPE2) has an essential role in immune homeostasis, yet the relationship between TIPE2 expression and allograft rejection has not been addressed. Dependent on clinical diagnosis, 96 kidney transplant recipients were divided into three groups, long-term survival group, acute rejection group (AR) and chronic rejection group (CR). Thirty-two healthy volunteers were used as a control group. The expression of TIPE2 in peripheral blood mononuclear cells (PBMC) and kidney biopsy samples was performed using reverse transcript-polymerase chain reaction, immunohistochemistry and immunofluorescence. The expression of TIPE2 in PBMC of CR group was significantly higher than that of the healthy control (P < 0.001), but TIPE2 expression in AR group was lower than that of control individuals (P < 0.05). The renal expression of TIPE2 in allograft tissue of CR was significantly lower and its expression in AR slightly lower than in normal kidneys. The positive correlation between TIPE2 expression in PBMCs and the CR of allo-kidney grafts indicates that detection of TIPE2 in the blood samples may be used as one of the diagnosis molecular markers in clinical monitoring kidney chronic rejection.
Assuntos
Rejeição de Enxerto/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/sangue , Transplante de Rim/imunologia , Doença Aguda , Adulto , Biomarcadores/sangue , Biópsia , Estudos de Casos e Controles , Doença Crônica , Feminino , Imunofluorescência , Regulação da Expressão Gênica , Rejeição de Enxerto/sangue , Rejeição de Enxerto/genética , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Adulto JovemRESUMO
Vascular complications after renal transplantation are one of the serious surgical complications, which can affect the transplantation outcome and even endanger life if not treated properly. We performed a retrospective analysis of the 2,304 renal transplantations procedures completed between the period of Jan., 2015 and Jan., 2022, which consisted of 1,658 male patients and 646 female patients. Among the above cases, there were 54 cases of vascular complications after renal transplantation, the incidence of vascular complications in our study was 2.34% (54/2,304), the most common vascular complication was transplanted renal artery stenosis (TRAS, n = 36), followed by external iliac artery dissection (n = 5), renal artery rupture (n = 4), renal vein thrombosis (n = 3), renal artery thrombosis (n = 2), renal artery dissection (n = 1), renal artery pseudoaneurysm (n = 1), and internal iliac artery pseudoaneurysm (n = 1), and renal artery kinking (n = 1). 40 patients were treated by percutaneous transluminal angioplasty (PTA), including 3 balloon catheter dilatation and 37 endovascular stentings, and 14 underwent open surgery. Eventually, 9 patients had graft nephrectomy, resulting in an overall treatment rate of 81.5%. Most vascular complications can be treated satisfactorily with PTA. However, the overall treatment of renal artery rupture, thrombosis, renal artery kinking, and other complications is poor, and the rate of transplanted renal loss is high.