RESUMEN
HLA-DPB1*1500:01N differs from HLA-DPB1*05:01:01:01 by one nucleotide in exon 3.
Asunto(s)
Cadenas beta de HLA-DP , Nucleótidos , Humanos , Alelos , Secuencia de Bases , China , Análisis de Secuencia de ADNRESUMEN
The microbiome in a specific human organ has been well-studied, but few reports have investigated the multi-organ microbiome as a whole. Here, we aim to analyse the intra-individual inter-organ and intra-organ microbiome in deceased humans. We collected 1608 samples from 53 sites of 7 surface organs (oral cavity, esophagus, stomach, small intestine, appendix, large intestine and skin; n = 33 subjects) and performed microbiome profiling, including 16S full-length sequencing. Microbial diversity varied dramatically among organs, and core microbial species co-existed in different intra-individual organs. We deciphered microbial changes across distinct intra-organ sites, and identified signature microbes, their functional traits, and interactions specific to each site. We revealed significant microbial heterogeneity between paired mucosa-lumen samples of stomach, small intestine, and large intestine. Finally, we established the landscape of inter-organ relationships of microbes along the digestive tract. Therefore, we generate a catalogue of bacterial composition, diversity, interaction, functional traits, and bacterial translocation in human at inter-organ and intra-organ levels.
Asunto(s)
Apéndice , Microbiota , Humanos , Traslocación Bacteriana , Estómago , Microbiota/genética , BocaRESUMEN
Reduced Na+/K+-ATPase (NKA) activity and NKAα1 expression are engaged in the pathologies of renal diseases. NKA-mediated Src activation is not the only reason for NKA-related renal fibrosis. In this study, we found that genetic reduction of NKAα1 exhibited exacerbated tubulointerstitial lesions and fibrosis in the UUO mice model. Activation of NKAα1 with an antibody against the extracellular DR region of the NKAα1 subunit (DRm217) prevented UUO-induced tubulointerstitial lesions, preserved kidney function, and decrease renal fibrosis. Further studies revealed that NKAα1 deficiency mice exhibited high inflammation factors expression when they suffered UUO surgery, compared with NKAα1+/+ (WT) mice. DRm217 alleviated inflammatory cell infiltration, suppress NF-κB phosphorylation, and decreased inflammatory factors expression in the UUO mice model. Released HMGB1 can trigger the inflammatory response and contribute to renal fibrosis. Knockdown of NKA in renal tubular cells or in NKAα1+/- mice was associated with more susceptibility to HMGB1 release in the UUO mice model. DRm217 exerted its antifibrotic effect via inhibiting HMGB1 release. Furthermore, AMPK activation participates in the effect of DRm217 on inhibiting HMGB1 release. Our findings suggest that NKAα1 is a regulator of renal fibrosis and its DR-region is a novel target on it.
Asunto(s)
Proteína HMGB1 , Enfermedades Renales , Obstrucción Ureteral , Ratones , Animales , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/genética , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Riñón/patología , Enfermedades Renales/patología , Anticuerpos Monoclonales/farmacología , FibrosisRESUMEN
Early apoptosis of grafted islets is one of the main factors affecting the efficacy of islet transplantation. The combined transplantation of islet cells and bone marrow mesenchymal stem cells (BMSCs) can significantly improve the survival rate of grafted islets. Transcription factor insulin gene enhancer binding protein 1 (ISL1) is shown to promote the angiogenesis of grafted islets and the paracrine function of mesenchymal stem cells during the co-transplantation, yet the regulatory mechanism remains unclear. By using ISL1-overexpressing BMSCs and the subtherapeutic doses of islets for co-transplantation, we managed to reduce the apoptosis and improve the survival rate of the grafts. Our metabolomics and proteomics data suggested that ISL1 upregulates aniline (ANLN) and Inhibin beta A chain (INHBA), and stimulated the release of caffeine in the BMSCs. We then demonstrated that the upregulation of ANLN and INHBA was achieved by the binding of ISL1 to the promoter regions of the two genes. In addition, ISL1 could also promote BMSCs to release exosomes with high expression of ANLN, secrete INHBA and caffeine, and reduce streptozocin (STZ)-induced islets apoptosis. Thus, our study provides mechanical insight into the islet/BMSCs co-transplantation and paves the foundation for using conditioned medium to mimic the ISL1-overexpressing BMSCs co-transplantation.
Asunto(s)
Exosomas , Insulinas , Islotes Pancreáticos , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Compuestos de Anilina/metabolismo , Apoptosis/genética , Cafeína/metabolismo , Cafeína/farmacología , Medios de Cultivo Condicionados , Subunidades beta de Inhibinas , Insulinas/metabolismo , Islotes Pancreáticos/metabolismo , Células Madre Mesenquimatosas/metabolismo , Estreptozocina/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: The complement system plays an important role in the immune response to transplantation, and the diagnostic significance of peritubular capillary (PTC) C4d deposition (C4d+) in grafts is controversial. The study aimed to fully investigate the risk factors for PTC C4d+ and analyze its significance in biopsy pathology of kidney transplantation. METHODS: This retrospective study included 124 cases of kidney transplant with graft biopsy and donor-specific antibody (DSA) testing from January 2017 to December 2019 in a single center. The effects of recipient pathological indicators, eplet mismatch (MM), and DSAs on PTC C4d+ were examined using univariate and multivariate logistic regression analyses. RESULTS: In total, 35/124 (28%) were PTC C4d+, including 21 with antibody-mediated rejection (AMR), eight with renal tubular injury, three with T cell-mediated rejection, one with glomerular disease, and two others. Univariate analysis revealed that DSAs (Pâ<â0.001), glomerulitis (Pâ<â0.001), peritubular capillaritis (Pâ<â0.001), and human leukocyte antigen (HLA) B eplet MM (Pâ=â0.010) were the influencing factors of PTC C4d+. According to multivariate analysis, DSAs (odds ratio [OR]: 9.608, 95% confidence interval [CI]: 2.742-33.668, Pâ<â0.001), glomerulitis (OR: 3.581, 95%CI: 1.246-10.289, Pâ=â0.018), and HLA B eplet MM (OR: 1.166, 95%CI: 1.005-1.353, Pâ=â0.042) were the independent risk factors for PTC C4d+. In receiver operating characteristic curve analysis, the area under the curve was increased to 0.831 for predicting PTC C4d+ when considering glomerulitis, DSAs, and HLA B eplet MM. The proportions of HLA I DSAs and PTC C4d+ in active antibody-mediated rejection were 12/17 and 15/17, respectively; the proportions of HLA class II DSAs and PTC C4d+ in chronic AMR were 8/12 and 7/12, respectively. Furthermore, the higher the PTC C4d+ score was, the more serious the urinary occult blood and proteinuria of recipients at the time of biopsy. CONCLUSIONS: PTC C4d+ was mainly observed in AMR cases. DSAs, glomerulitis, and HLA B eplet MM are the independent risk factors for PTC C4d+.
Asunto(s)
Trasplante de Riñón , Aloinjertos , Biopsia , Complemento C4b , Rechazo de Injerto , Antígenos HLA , Antígenos HLA-B , Humanos , Trasplante de Riñón/efectos adversos , Fragmentos de Péptidos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Revascularization of the islet transplant is a crucial step that defines the success rate of patient recovery. Bone marrow-derived mesenchymal stem cells (BMSCs) have been reported to promote revascularization; however, the underlying cellular mechanism remains unclear. Moreover, our liquid chromatography-tandem mass spectrometry results showed that BMSCs could promote the expression of insulin gene enhancer binding protein-1 (ISL1) in islets. ISL1 is involved in islets proliferation and plays a potential regulatory role in the revascularization of islets. This study identifies the ISL1 protein as a potential modulator in BMSCs-mediated revascularization of islet grafts. We demonstrated that the survival rate and insulin secretion of islets were increased in the presence of BMSCs, indicating that BMSCs promote islet revascularization in a coculture system and rat diabetes model. Interestingly, we also observed that the presence of BMSCs led to an increase in ISL1 and vascular endothelial growth factor A (VEGFA) expression in both islets and the INS-1 rat insulinoma cell line. In silico protein structure modeling indicated that ISL1 is a transcription factor that has four binding sites with VEGFA mRNA. Further results showed that overexpression of ISL1 increased both the abundance of VEGFA transcripts and protein accumulation, while inhibition of ISL1 decreased the abundance of VEGFA. Using a ChIP-qPCR assay, we demonstrated that direct molecular interactions between ISL1 and VEGFA occur in INS-1 cells. Together, these findings reveal that BMSCs promote the expression of ISL1 in islets and lead to an increase in VEGFA in islet grafts. Hence, ISL1 is a potential target to induce early revascularization in islet transplantation.
Asunto(s)
Trasplante de Islotes Pancreáticos , Islotes Pancreáticos , Células Madre Mesenquimatosas , Animales , Médula Ósea/metabolismo , Humanos , Islotes Pancreáticos/metabolismo , Trasplante de Islotes Pancreáticos/métodos , Células Madre Mesenquimatosas/metabolismo , Ratas , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Proteasome inhibitor bortezomib offers one more option for acute or chronic antibody-mediated rejection after kidney transplantation, but aggravated acute kidney injury (AKI) in some cases early after surgery using bortezomib bring new problem. Here, we evaluated the effects of bortezomib and ONX-0914 on renal tubule injury in a mouse model of ischemia-reperfusion injury. After treated with bortezomib, serum creatinine, usea nitrogen and tubular necrosis significantly increased compared with vehicle-treated mice, but decreased in ONX-0914 group mildly. Infiltration of neutrophil and macrophage were less in bortezomib and ONX-0914-treated mice than vehicle-treated group, and the same was observed on oxidative stress in the kidneys. Furthermore, the apoptosis of renal tubular epithelial cells increased in bortezomib-treated mice' kidneys compared with ONX-0914 and vehicle-treated controls. In vitro HK2 cell experiments also demonstrated the proapoptotic effect of bortezomib. The mRNA expression of several proapoptotic factors increased in kidneys of bortezomib-treated mice. In brief, bortezomib, as a proteasome inhibitor, shows a certain cytotoxicity to renal tubular epithelial cell during ischemia/reperfusion injury (IRI) through increased apoptosis. ONX-0914, as an immunoproteasome inhibitor, showed equal potency on anti-inflammation and oxidative stress relieving compared with bortezomib, while less cytotoxicity. The results render the immunoproteasome is a better target for anti-rejection and protecting kidney function in the field of organ transplantation.
RESUMEN
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.
Asunto(s)
Funcionamiento Retardado del Injerto/diagnóstico , Trasplante de Riñón/efectos adversos , Complicaciones Posoperatorias/diagnóstico , Donantes de Tejidos , Adulto , Área Bajo la Curva , China , Creatinina/sangre , Funcionamiento Retardado del Injerto/epidemiología , Femenino , Tasa de Filtración Glomerular , Supervivencia de Injerto , Paro Cardíaco , Humanos , Terapia de Inmunosupresión/métodos , Inmunosupresores/uso terapéutico , Incidencia , Estimación de Kaplan-Meier , Riñón/fisiología , Trasplante de Riñón/mortalidad , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Sensibilidad y Especificidad , Factores de Tiempo , Resultado del TratamientoRESUMEN
B cell activating factor (BAFF) belonging to TNF family is a cytokine that enhances B-cell proliferation and differentiation. Recently, It has been suggested that BAFF might be a potential therapeutic target for treating autoimmune disease. However, the relationship between BAFF and allograft rejection is controversial, and the clinical significance of BAFF in predicting allograft rejection need to be further explored. We conducted 6-month follow-up study to confirm the hypothesis that BAFF might be a risk factor for predicting acute rejection in kidney transplant recipients. At the end of the study, a total of 155 kidney transplant recipients were recruited from October 2015 to October 2017, and classified into acute rejection group (n = 34) and stable renal function group (n = 121) according to their clinical course. We demonstrate that the serum BAFF levels when acute rejection occurred was significantly higher than that in the stable renal function group (2426.19 ± 892.19 vs. 988.17 ± 485.63 pg/mL, P < 0.05). BAFF expression was significantly enhanced in the membrane and cytoplasm of renal tubule epithelial cells in the transplant kidney tissue with acute rejection, and a positive correlation between BAFF and C4d expression was also observed (r = 0.880, P = 0.001). ROC analyses highlight the superiority of serum BAFF level before transplant over those on other post-transplant days in prediction of acute rejection episodes. The sensitivity, specificity and AUC (area under curve) were 83.3, 89.5, and 0.886%, respectively. Kaplan-Meier survival analysis showed that recipients with higher pretransplant BAFF levels had higher acute rejection incidence (P = 0.003). In conclusion, we have identified that BAFF levels are associated with the acute rejection and could be a promising biomarker to predict kidney transplant rejection risks.
Asunto(s)
Factor Activador de Células B/sangre , Rechazo de Injerto/sangre , Rechazo de Injerto/epidemiología , Trasplante de Riñón/efectos adversos , Adulto , Biomarcadores/sangre , Complemento C4b/metabolismo , Femenino , Estudios de Seguimiento , Rechazo de Injerto/inmunología , Supervivencia de Injerto/inmunología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/metabolismo , Periodo Preoperatorio , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Receptores de Trasplantes , Adulto JovenRESUMEN
BACKGROUND: Kidney transplant is always emergent operations and frequently need to be performed at nighttime to reduce cold ischemia time (CIT). Previous studies have revealed that fatigue and sleep deprivation can result in adverse consequences of medical procedures. This study aimed to evaluate whether nighttime operation has adverse impact on kidney transplant. METHODS: A retrospective analysis of recipients accepted kidney transplant from deceased donors in one center from 2014 to 2016 was performed. Daytime transplant was defined as operation started after 8 AM or ended before 8 PM and nighttime operation was defined as operation ended after 8 PM or started before 8 AM. The incidences of complications such as delayed graft function, acute rejection, surgical complications and nosocomial infections were compared between 2 groups. Student's t-test was used to analyze continuous variables such as serum creatinine (Scr) at 1-year of post-transplant. The Chi-square test was used to analyze categorical variables. Differences in recipients and graft survival were analyzed using Kaplan-Meier methodology and log-rank tests. RESULTS: Among the 443 recipients, 233 (52.6%) were classified into the daytime group and the others 210 (47.4%) were in the nighttime group. The 1-year survival rate of recipients was similar for the recipients in the daytime and nighttime groups (95.3% vs. 95.2%, Pâ=â0.981). Although the 1-year graft survival rate in the nighttime group was slightly superior to that in the daytime group, the difference was not significant (92.4% vs. 88.4%, Pâ=â0.164). Furthermore, Scr and incidence of complications were also not significantly different between the 2 groups. CONCLUSIONS: Our results suggested that operation time of kidney transplant with short CIT has no significant impact on the outcome of kidney transplant. Nighttime operation of kidney transplant with short CIT could be postponed to the following day to alleviate the burden on medical staffs and avoid the potential risk.
Asunto(s)
Trasplante de Riñón/mortalidad , Adulto , Cadáver , Isquemia Fría , Femenino , Supervivencia de Injerto , Humanos , Trasplante de Riñón/efectos adversos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Factores de TiempoRESUMEN
BACKGROUND: Hypothermic machine perfusion (HMP) is being used more often in cardiac death kidney transplantation; however, the significance of assessing organ quality and predicting delayed graft function (DGF) by HMP parameters is still controversial. Therefore, we used a readily available HMP variable to design a scoring model that can identify the highest risk of DGF and provide the guidance and advice for organ allocation and DCD kidney assessment. METHODS: From September 1, 2012 to August 31, 2016, 366 qualified kidneys were randomly assigned to the development and validation cohorts in a 2:1 distribution. The HMP variables of the development cohort served as candidate univariate predictors for DGF. The independent predictors of DGF were identified by multivariate logistic regression analysis with a P < 0.05. According to the odds ratios (ORs) value, each HMP variable was assigned a weighted integer, and the sum of the integers indicated the total risk score for each kidney. The validation cohort was used to verify the accuracy and reliability of the scoring model. RESULTS: HMP duration (OR = 1.165, 95% confidence interval [CI]: 1.008-1.360, P = 0.043), resistance (OR = 2.190, 95% CI: 1.032-10.20, P < 0.001), and flow rate (OR = 0.931, 95% CI: 0.894-0.967, P = 0.011) were the independent predictors of identified DGF. The HMP predictive score ranged from 0 to 14, and there was a clear increase in the incidence of DGF, from the low predictive score group to the very high predictive score group. We formed four increasingly serious risk categories (scores 0-3, 4-7, 8-11, and 12-14) according to the frequency associated with the different risk scores of DGF. The HMP predictive score indicates good discriminative power with a c-statistic of 0.706 in the validation cohort, and it had significantly better prediction value for DGF compared to both terminal flow (P = 0.012) and resistance (P = 0.006). CONCLUSION: The HMP predictive score is a good noninvasive tool for assessing the quality of DCD kidneys, and it is potentially useful for physicians in making optimal decisions about the organs donated.
Asunto(s)
Funcionamiento Retardado del Injerto , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/métodos , Adulto , Femenino , Humanos , Inmunosupresores/uso terapéutico , Modelos Logísticos , Masculino , Análisis Multivariante , Oportunidad Relativa , Preservación de ÓrganosRESUMEN
BACKGROUND: Vascular resistance and flow rate during hypothermic machine perfusion (HMP) of kidneys is correlated with graft function. We aimed to determine the effects of increasing HMP pressure versus maintaining the initial pressure on kidney transplantation outcomes. METHODS: We retrospectively reviewed the data of 76 primary transplantation patients who received HMP-preserved kidneys from 48 donors after cardiac death between September 1, 2013, and August 31, 2015. HMP pressure was increased from 30 to 40 mmHg (1 mmHg = 0.133 kPa) in kidneys with poor flow and/or vascular resistance (increased pressure [IP] group; 36 patients); otherwise, the initial pressure was maintained (constant pressure group; 40 patients). Finally, the clinical characteristics and transplantation outcomes in both groups were assessed. RESULTS: Delayed graft function (DGF) incidence, 1-year allograft, patient survival, kidney function recovery time, and serum creatinine level on day 30 were similar in both groups, with improved flow and resistance in the IP group. Among patients with DGF, kidney function recovery time and DGF duration were ameliorated in the IP group. Multivariate logistic regression analysis revealed that donor hypertension (odds ratio [OR]: 1.43, 95% confidence interval [CI]: 1.02-2.06, P = 0.035), donor terminal serum creatinine (OR: 1.27, 95% CI: 1.06-1.62, P = 0.023), warm ischemic time (OR: 3.45, 95% CI: 1.97-6.37, P = 0.002), and terminal resistance (OR: 3.12, 95% CI: 1.76-6.09, P = 0.012) were independent predictors of DGF. Cox proportional hazards analysis showed that terminal resistance (hazard ratio: 2.06, 95% CI: 1.32-5.16, P = 0.032) significantly affected graft survival. CONCLUSION: Increased HMP pressure improves graft perfusion but does not affect DGF incidence or 1-year graft survival.
Asunto(s)
Trasplante de Riñón/métodos , Adulto , Aloinjertos , Funcionamiento Retardado del Injerto , Femenino , Humanos , Hipertensión/fisiopatología , Pruebas de Función Renal , Modelos Logísticos , Masculino , Persona de Mediana Edad , Preservación de Órganos , Estudios Retrospectivos , Donantes de TejidosRESUMEN
Biomarkers are urgently required for predicting rejection so that anti-rejection treatment can be taken early to protect the allograft from irreversible damage. We hypothesized that the combination of circulating fractalkine, IFN-γ and IP-10 might serve as effective biomarkers for predicting early acute renal allograft rejection. We conducted a retrospective study of 87 subjects, who were classified into acute rejection group (ARG; nâ¯=â¯38) and non-rejection group (NRG; nâ¯=â¯49). Serum fractalkine, IFN-γ and IP-10 levels were measured by Luminex. The levels of fractalkine on day 0 and 7th day, IP-10 on 4th and 7th day, and IFN-γ on 7th day in ARG was significantly higher than that in NRG. Kaplan-Meier survival analysis highlighted the higher-levels groups of fractalkine on day 0, 4th and 7th day, IFN-γ on day 0, 1st, 4th, and 7th day and IP-10 on the 4th and 7th day in rejection-free survival probability were significantly lower than low-levels groups. ROC analyses highlight the superiority of fractalkine on day 0, IP-10 on day 0, 4th and 7th day, and IFN-γ on day 0, 1st and 7th day in prediction of acute rejection. We found the combination of fractalkine on day 0, IP-10 on 7th day and IFN-γ on 7th day had the highest AUC (0.866) for predicting rejection with a sensitivity of 86.8% and a specificity of 89.8%. Our findings demonstrated a more powerful prediction of early acute renal allograft rejection during the first month after transplantation by combination of multiple-biomarkers of fractalkine, IFN-γ and IP-10, and the results might help stratify the immunologic risk of acute allograft rejection in recipients.
Asunto(s)
Biomarcadores/sangre , Quimiocina CX3CL1/sangre , Quimiocina CXCL10/sangre , Rechazo de Injerto/diagnóstico , Interferón gamma/sangre , Trasplante de Riñón , Enfermedad Aguda , Adulto , China/epidemiología , Enfermedad Crónica , Femenino , Rechazo de Injerto/epidemiología , Rechazo de Injerto/mortalidad , Humanos , Masculino , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Trasplante HomólogoRESUMEN
Arctigenin (ATG) is one of the main active substances in fruit derived from Arctium lappa L. Previous studies have reported that ATG have antitumor, neuroprotective, antioxidant, antifibrosis and anti-inflammatory functions. However, the actions of ATG in kidney with acute injury following ischemia/ reperfusion (I/R) is still uncertain. In our study, mice were subjected to kidney I/R by having the kidney pedicles clamped and administered with vehicle or ATG (1, 3 or 9â¯mg/kg/d) via oral gavage for 7 consecutive days prior to I/R. Notably, ATG aggravated kidney I/R injury with the concentration increases. Multiple biochemical assays and histological examination showed ATG significantly alleviated the inflammatory response as reflected by a decreased expression of proinflammatory cytokine, TLR4/MyD88, and NF-κB, along with the infiltration of CD68+ macrophage and CD11b+Gr1+ neutrophil in the kidneys. Meanwhile, ATG alleviated I/R-induced oxidative stress proved by increasing kidney manganese superoxide dismutase and glutathione peroxidase activity but reducing levels of malonaldehyde and inducible nitric oxide synthase. On the contrary, apoptosis was significantly increased in kidneys of ATG-treated mice compared with vehicle-treated controls, especially in tubular cells. There were increased numbers of TUNEL positive cells and increased Bcl-2, Bax, cleaved-caspase-3, and cleaved-caspase-9 expression. The current study demonstrates that pretreatment of ATG aggravates I/R induced acute kidney injury by increasing apoptosis of tubular cells despite reducing infiltrating inflammatory cells and proinflammatory cytokine.
Asunto(s)
Lesión Renal Aguda/prevención & control , Antiinflamatorios/uso terapéutico , Apoptosis/efectos de los fármacos , Furanos/uso terapéutico , Riñón/efectos de los fármacos , Lignanos/uso terapéutico , Daño por Reperfusión/tratamiento farmacológico , Lesión Renal Aguda/etiología , Lesión Renal Aguda/patología , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/efectos adversos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Furanos/administración & dosificación , Furanos/efectos adversos , Inflamación , Riñón/inmunología , Riñón/metabolismo , Riñón/patología , Lignanos/administración & dosificación , Lignanos/efectos adversos , Masculino , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Daño por Reperfusión/complicaciones , Daño por Reperfusión/patologíaRESUMEN
BACKGROUND: Immunosuppressive agents are still inefficient in preventing biopsy-proven acute rejection (BPAR) after expanded criteria donor (ECD) kidney transplantation. The aim of this study was to investigate the relationships between early immunosuppressive exposure and the development of BPAR. METHODS: We performed a retrospective study of 58 recipients of ECD kidney transplantation treated with enteric-coated-mycophenolate sodium, tacrolimus (Tac), and prednisone. The levels of mycophenolic acid-area under the curve (MPA-AUC)0-12h and Tac C0were measured at the 1st week and the 1st month posttransplant, respectively. The correlation was assessed by multivariate logistic regression. RESULTS: The occurrence rates of BPAR and antibody-mediated rejection were 24.1% and 10.3%, respectively. A low level of MPA-AUC0-12h at the 1st week posttransplant was found in BPAR recipients (38.42 ± 8.37 vs. 50.64 ± 13.22, P < 0.01). In addition, the incidence of BPAR was significantly high (P < 0.05) when the MPA-AUC0-12hlevel was <30 mg·h-1·L-1 at the 1st week (15.0% vs. 44.4%) or the Tac C0was <4 ng/ml at the 1st month posttransplant (33.3% vs. 21.6%). Multivariable logistic regression analysis showed that the MPA-AUC0-12h at the 1st week (OR: 0.842, 95% CI: 0.784-0.903) and the Tac C0at the 1st month (OR: 0.904, 95% CI: 0.822-0.986) had significant inverse correlation with BPAR (P < 0.05). CONCLUSIONS: Low-level exposure of MPA and Tac C0in the early weeks posttransplant reflects an increased acute rejection risk, which suggested that MPA-AUC0-12h <30 mg·h-1·L-1 and Tac C0 <4 ng/ml should be avoided in the first few weeks after transplantation.
Asunto(s)
Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Inmunosupresores/uso terapéutico , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/métodos , Ácido Micofenólico/uso terapéutico , Tacrolimus/uso terapéutico , Adulto , Femenino , Humanos , Inmunosupresores/química , Masculino , Persona de Mediana Edad , Ácido Micofenólico/química , Estudios Retrospectivos , Tacrolimus/química , Factores de TiempoRESUMEN
NLRC5, as the largest member of nucleotide-binding domain and leucine-rich repeat (NLR) family, was involved in various physiological processes, such as inflammation, fibrosis, innate immunity and diabetic nephropathy. However, the role of NLRC5 in acute kidney injury remains unclear. The aim of this study was to investigate the role of NLRC5 in human renal proximal tubular epithelial cells (HK-2) exposed to hypoxia/reoxygenation (H/R). Our results demonstrated that the expression of NLRC5 was significantly up-regulated in HK-2 cells exposed to H/R. Knockdown of NLRC5 significantly improved the viability of HK-2 cells exposed to H/R. In addition, knockdown of NLRC5 efficiently inhibited H/R-induced oxidative stress and apoptosis in HK-2 cells. Mechanistically, knockdown of NLRC5 markedly enhanced the activation of PIK3/Akt signaling pathway in H/R-stimulated HK-2 cells. In summary, our findings indicate that knockdown of NLRC5 attenuates renal I/R injury in vitro through the activation of PI3K/Akt signaling pathway.
Asunto(s)
Técnicas de Silenciamiento del Gen , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Riñón/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Daño por Reperfusión/patología , Transducción de Señal , Apoptosis/genética , Línea Celular , Supervivencia Celular/genética , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Estrés Oxidativo , Daño por Reperfusión/genética , Regulación hacia Arriba/genéticaRESUMEN
Macrophages have a diverse set of functions based upon their activation states. The activation states, including resting (M0) and polarizing (M1 and M2) states, of macrophages derived from the mouse bone marrow, spleen, and peritoneal cavity (BMs, SPMs, and PCMs, respectively) were compared. We evaluated the macrophage yield per mouse and compared the surface markers major histocompatibility complex (MHC) II and CD86 by flow cytometry. The relative mRNA levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, mannose receptor (MR), and Ym1 in the M0, M1, and M2 states were also compared using real-time polymerase chain reaction (PCR) analysis. Bone marrow yielded the most macrophages with the best homogeneity, but they were polarized toward the M2 phenotype. All three types of macrophages had the capacity to polarize into the M1 and M2 states, but SPMs had a stronger capacity to polarize into M1. The three types of macrophages showed no differences in their capacity to polarize into the M2 state. Therefore, the three types of macrophages have distinct characteristics regardless of their resting or polarizing states. Although bone marrow can get large amounts of homogeneous macrophages, the macrophages cannot replace tissue-derived macrophages.
Asunto(s)
Células de la Médula Ósea/citología , Macrófagos/citología , Cavidad Peritoneal/citología , Bazo/citología , Animales , Antígeno B7-2/metabolismo , Citometría de Flujo , Genes MHC Clase II , Complejo Mayor de Histocompatibilidad , Masculino , Ratones , Ratones Endogámicos BALB C , Fenotipo , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
BACKGROUND: How to evaluate the quality of donation after cardiac death (DCD) kidneys has become a critical problem in kidney transplantation in China. Hence, the aim of this study was to develop a simple donor risk score model to evaluate the quality of DCD kidneys before DCD. METHODS: A total of 543 qualified kidneys were randomized in a 2:1 manner to create the development and validation cohorts. The donor variables in the development cohort were considered as candidate univariate predictors of delayed graft function (DGF). Multivariate logistic regression was then used to identify independent predictors of DGF with P < 0.05. Date from validation cohort were used to validate the donor scoring model. RESULTS: Based on the odds ratios, eight identified variables were assigned a weighted integer; the sum of the integer was the total risk score for each kidney. The donor risk score, ranging from 0 to 28, demonstrated good discriminative power with a C-statistic of 0.790. Similar results were obtained from validation cohort with C-statistic of 0.783. Based on the obtained frequencies of DGF in relation to different risk scores, we formed four risk categories of increasing severity (scores 0-4, 5-9, 10-14, and 15-28). CONCLUSIONS: The scoring model might be a good noninvasive tool for assessing the quality of DCD kidneys before donation and potentially useful for physicians to make optimal decisions about donor organ offers.
Asunto(s)
Muerte , Funcionamiento Retardado del Injerto/fisiopatología , Adulto , Femenino , Humanos , Trasplante de Riñón , Modelos Logísticos , Masculino , Persona de Mediana Edad , Donantes de Tejidos , Recolección de Tejidos y Órganos/métodos , Obtención de Tejidos y Órganos/métodosRESUMEN
OBJECTIVE: This study aims to investigate the regulatory mechanism of 1,25-(OH)2D3 on the proliferation of fibroblast-like synoviocytes (FLS) and expressions of pro-inflammatory cytokines in rheumatoid arthritis (RA) rats via microRNA-22 (miR-22). METHODS: A rat model of RA was established with a subcutaneous injection of type II collagen. After treated with different concentrations of 1,25-(OH)2D3 the proliferation of FLS was estimated by the MTT method, and the optimal concentration of 1,25-(OH)2D3 was selected for further experiments. Cell proliferation was detected by MTT. Cell cycle and apoptosis were analyzed by FCM. The IL-1ß, IL-6, IL-8, and PGE2 protein expressions were determined by ELISA, and MMP-3, INOS, and Cox-2 mRNA expressions were measured by qRT-PCR. RESULTS: The rat model of RA was successfully established. Compared with the blank group, the 1,25-(OH)2D3 and miR-22 inhibitors groups exhibited higher proliferation inhibition and apoptosis rates, lower levels of pro-inflammatory cytokines (IL-1ß, IL-6, IL-8, and PGE2), and decreased mRNA expressions of MMP-3, INOS, and Cox-2. The miR-22 mimics group had lower proliferation inhibition and apoptosis rates, elevated expressions of pro-inflammatory cytokines and MMP-3, INOS, and Cox-2 than the blank group. In contrast to the 1,25-(OH)2D3 group, the proliferation inhibition and apoptosis rates were down-regulated, and the expressions of pro-inflammatory cytokines and MMP-3, INOS, and Cox-2 were up-regulated in the 1,25-(OH)2D3 + miR-22 mimics group. CONCLUSION: Our study demonstrated that 1,25-(OH)2D3 inhibits the proliferation of FLS and alleviates inflammatory response in RA rats by down-regulating miR-22.