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INTRODUCTION: No studies explored the long-term outcomes of neural cell adhesion molecule 1 (NCAM1) associated membranous lupus nephritis (MLN) patients. METHOD: We performed immunohistochemical studies on kidney biopsy specimens against NCAM1 in consecutive MLN patients. The clinical and histopathological characteristics and outcomes of cases of NCAM1 associated MLN patients are described and compared with NCAM1 negative patients. In addition, we detected serum circulating anti-NCAM1 antibodies through western blotting and indirect immunofluorescence assays. RESULTS: Among 361 MLN cases, 18 (5.0%) were glomerular NCAM1-positive. NCAM1 positive MLN patients were older [35 years (IQR 27-43) versus 28 (22-37); P = 0.050) and had lower systemic lupus erythematosus disease activity index [11 (IQR 8-12) versus 14 (10-18); P = 0.007], serum creatinine [60 µmol/L (IQR 50-70) versus 70 (54-114); P = 0.029], activity index [3 (IQR 2-6) versus 6 (3-9); P = 0.045] at kidney biopsy compared with NCAM1 negative patients. The percentage of positive anti-Sjogren's syndrome related antigen A antibodies in NCAM1 positive patients was significantly greater (83.3% versus 58.2%; P = 0.035) than in the NCAM1 negative patients. However, no evidence of neuropsychiatric disorders was found in these 18 patients. There were no significant differences in the treatment response and the risk of end stage renal diseases between NCAM1 positive and negative groups (P = 0.668 and P = 0.318, respectively). But the risk of death was much higher in the NCAM1 positive group than the NCAM1 negative group (27.8% vs. 8.1%, P = 0.007). Moreover, the risk of death was also much higher in the NCAM1 positive group than the matched NCAM1 negative group (Log-rank P = 0.013). Additionally, circulating anti-NCAM1 antibodies can be detected in 1/5 (20%) patients who had serum available. CONCLUSION: The prevalence of NCAM1 positivity was 5.0% in our cohort of MLN and the high mortality in these subgroup patients are needed to validate in future studies.
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INTRODUCTION: Acute kidney injury (AKI) is common in lupus nephritis (LN) and a risk factor for chronic kidney failure. Here, we aimed to assess the characteristics and prognosis of LN patients with AKI. METHODS: AKI and AKI severity stages in LN patients were defined by the Kidney Disease Improving Global Outcomes (KDIGO) classification. Long-term renal outcomes and patient mortality between different stages of AKI were compared by Cox regression analysis. RESULTS: Of 1272 LN patients, 225 (17.69%) had AKI and 72 (5.66%) were AKI stage 3. Compared with the non-AKI group, the proportion of male patients was significantly higher in the AKI group (p = 0.002). In addition, there were markedly higher proportions of hematologic system damage, more severe renal manifestations, and higher Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores in the AKI group than in the non-AKI group. The active and chronic lesions in renal biopsy were significantly higher in LN patients with AKI than those without AKI. During a median follow-up of 53 months, Kaplan-Meier curve showed that LN patients with AKI stage 3 had significantly poorer long-term renal outcomes (p = 0.002) and patient survival (p < 0.001) than those without AKI. Furthermore, AKI stage 3, but not stage 1 or 2 was significantly associated with adverse renal outcomes (hazard ratio [HR] = 2.52, 95% confidence interval [CI] 1.01-6.28, p = 0.048) and all-cause mortality (HR = 2.80, 95% CI: 1.18-6.61, p = 0.019) in LN patients. In patients with AKI, increased baseline serum creatinine and severe glomerular sclerosis were independent risk factors for worse renal outcomes, while higher blood pressure, increased baseline serum creatinine, and anti-Sjogren's syndrome A positivity could indicate poor survival. DISCUSSION: LN patients with AKI stage 3, but not stages 1 and 2, have poorer long-term renal outcomes and patient survival. Our study demonstrates the importance of early identification and management of AKI in LN patients.
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Injúria Renal Aguda , Nefrite Lúpica , Humanos , Masculino , Nefrite Lúpica/patologia , Creatinina , Rim/patologia , Prognóstico , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Estudos RetrospectivosRESUMO
Renal ischemia-reperfusion (I/R) injury is associated with markedly reduced protein expression of aquaporins (AQPs). Membrane G protein-coupled bile acid receptor-1 (TGR5) has shown protective roles in some kidney diseases. The purpose of the current study was to investigate whether activation of TGR5 prevented the decreased protein expression of AQPs in rodents with renal I/R injury and potential mechanisms. TGR5 agonist lithocholic acid (LCA) treatment reduced polyuria after renal I/R injury in rats. LCA prevented the decreased abundance of AQP2 protein and upregulated hypoxia-inducible factor (HIF)-1α protein expression, which were associated with decreased protein abundance of NF-κB p65 and IL-1ß. After renal I/R, mice with tgr5 gene deficiency exhibited further decreases in AQP2 and HIF-1α protein abundance and increases of IL-1ß and NF-κB p65 protein expression compared with wild-type mice. In primary cultured inner medullary collecting duct cells with hypoxia/reoxygenation, LCA induced markedly increased protein expression of AQP2 and HIF-1α, which were partially prevented by the PKA inhibitor H89. FG4592, a prolyl-4-hydroxylase domain-containing protein inhibitor, increased HIF-1α and AQP2 protein abundance in association with decreased NF-κB p65 protein expression in inner medullary collecting duct cells with hypoxia/reoxygenation. In conclusion, TGR5 stimulation by LCA prevented downregulation of renal AQPs in kidney with I/R injury, likely through activating HIF-1α signaling and suppressing inflammatory responses.NEW & NOTEWORTHY Stimulation of the membrane G protein-coupled bile acid receptor TGR5 by lithocholic acid (LCA) reduced polyuria in rats with renal ischemia-reperfusion (I/R) injury. LCA increased abundance of aquaporin-2 (AQP2) protein and upregulated hypoxia-inducible factor (HIF)-1α protein expression in association with decreased NF-κB p65 and IL-1ß. After I/R, mice with tgr5 gene deficiency exhibited more severe decreases in AQP2 and HIF-1α protein abundance and inflammatory responses. TGR5 activation exhibits a protective role in acute renal injury induced by I/R.
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Aquaporina 2/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Nefropatias/metabolismo , Rim/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Rim/patologia , Nefropatias/genética , Nefropatias/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ratos Wistar , Receptores Acoplados a Proteínas G/genética , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Fator de Transcrição RelA/metabolismoRESUMO
Increasing evidence supports the important role of H2S in renal physiology and the pathogenesis of kidney injury. Whether H2S regulates water metabolism in the kidney and the potential mechanism are still unknown. The present study was conducted to determine the role of H2S in urine concentration. Inhibition of both cystathionine-γ-lyase (CSE) and cystathionine-ß-synthase (CBS), 2 major enzymes for endogenous H2S production, with propargylglycine (PPG) and amino-oxyacetate (AOAA), respectively, caused increased urine output and reduced urine osmolality in mice that was associated with decreased expression of aquaporin (AQP)-2 in the renal inner medulla. Mice treated with both PPG and AOAA developed a urine concentration defect in response to dehydration that was accompanied by reduced AQP-2 protein expression. Inhibition of CSE alone was associated with a mild decrease in AQP-2 protein level in the renal medulla of heterozygous CBS mice. GYY4137, a slow H2S donor, markedly improved urine concentration and prevented the down-regulation of renal AQP-2 protein expression in mice with lithium-induced nephrogenic diabetes insipidus (NDI). GYY4137 significantly increased cAMP levels in cell lysates prepared from inner medullary collecting duct (IMCD) suspensions. AQP-2 protein expression was also upregulated, but was significantly inhibited by the adenyl cyclase inhibitor MDL12330A or the PKA inhibitor H89, but not the vasopressin 2 receptor (V2R) antagonist tolvaptan. Inhibition of endogenous H2S production impaired urine concentration in mice, whereas an exogenous H2S donor improved urine concentration in lithium-induced NDI by increasing AQP-2 expression in the collecting duct principal cells. H2S upregulated AQP-2 protein expression, probably via the cAMP-PKA pathway.-Luo, R., Hu, S., Liu, Q., Han, M., Wang, F., Qiu, M., Li, S., Li, X., Yang, T., Fu, X., Wang, W., Li, C. Hydrogen sulfide upregulates renal AQP-2 protein expression and promotes urine concentration.
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Aquaporina 2/metabolismo , Cistationina beta-Sintase/fisiologia , Cistationina gama-Liase/fisiologia , Sulfeto de Hidrogênio/farmacologia , Medula Renal/metabolismo , Micção/efeitos dos fármacos , Urina/química , Alcinos/metabolismo , Ácido Amino-Oxiacético/metabolismo , Animais , Gasotransmissores/farmacologia , Glicina/análogos & derivados , Glicina/metabolismo , Medula Renal/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , UrináliseRESUMO
Emerging evidence has shown that bile acids play important roles in renal physiology and diseases by activating two major receptors, the nuclear farnesoid X receptor (FXR) and the membrane G protein-coupled bile acid receptor-1 (Gpbar1; also known as TGR5). Both FXR and TGR5 have been identified in human and rodent kidneys, where they are deeply involved in renal water handling. In mice, FXR- or TGR5-related gene deficiency has been associated with reduced aquaporin-2 expression accompanied with impaired urinary concentration ability. In this mini-review, we briefly discuss the current understanding of FXR/TGR5 signaling in the kidneys, with a special focus on the regulation of aquaporin-2 expression by bile acids in the collecting ducts and its potential significance in disease conditions.
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Ácidos e Sais Biliares/metabolismo , Rim/metabolismo , Equilíbrio Hidroeletrolítico , Água/metabolismo , Animais , Aquaporina 2/metabolismo , Humanos , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: The bile acid-activated receptors, including the membrane G protein-coupled receptor TGR5 and nuclear farnesoid X receptor (FXR), have roles in kidney diseases. In this study, we investigated the role of TGR5 in renal water handling and the underlying molecular mechanisms. METHODS: We used tubule suspensions of inner medullary collecting duct (IMCD) cells from rat kidneys to investigate the effect of TGR5 signaling on aquaporin-2 (AQP2) expression, and examined the in vivo effects of TGR5 in mice with lithium-induced nephrogenic diabetes insipidus (NDI) and Tgr5 knockout (Tgr5-/-) mice. RESULTS: Activation of TGR5 by lithocholic acid (LCA), an endogenous TGR5 ligand, or INT-777, a synthetic TGR5-specific agonist, induced AQP2 expression and intracellular trafficking in rat IMCD cells via a cAMP-protein kinase A signaling pathway. In mice with NDI, dietary supplementation with LCA markedly decreased urine output and increased urine osmolality, which was associated with significantly upregulated AQP2 expression in the kidney inner medulla. Supplementation with endogenous FXR agonist had no effect. In primary IMCD suspensions from lithium-treated rats, treatment with INT-767 (FXR and TGR5 dual agonist) or INT-777, but not INT-747 (FXR agonist), increased AQP2 expression. Tgr5-/- mice exhibited an attenuated ability to concentrate urine in response to dehydration, which was associated with decreased AQP2 expression in the kidney inner medulla. In lithium-treated Tgr5-/- mice, LCA treatment failed to prevent reduction of AQP2 expression. CONCLUSIONS: TGR5 stimulation increases renal AQP2 expression and improves impaired urinary concentration in lithium-induced NDI. TGR5 is thus involved in regulating water metabolism in the kidney.
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Aquaporina 2/metabolismo , Túbulos Renais Coletores/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Água/metabolismo , Animais , Aquaporina 2/genética , Ácidos e Sais Biliares/farmacologia , Células Cultivadas , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/farmacologia , Ácidos Cólicos/farmacologia , Diabetes Insípido Nefrogênico/metabolismo , Homeostase , Túbulos Renais Coletores/efeitos dos fármacos , Ácido Litocólico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/deficiência , Receptores Acoplados a Proteínas G/genética , Transdução de SinaisRESUMO
The goal of this study is to evaluate PD-L1 prevalence and its association with major clinical characteristics in Chinese non-small cell lung cancer (NSCLC) patients to inform the clinical development of anti-PD1/PD-L1 agents in this population. We used phosphatase and tensin homolog (PTEN) expression through IHC as a surrogate tissue quality marker to screen surgical NSCLC samples in tissue microarray (TMA; 172 cases) or whole-section (268 cases) format. The samples were then analyzed with a clinically validated PD-L1 IHC assay. The results were correlated with baseline characteristics and clinical outcomes. PTEN IHC showed that 108 TMA samples and 105 whole-section samples qualified for PD-L1 IHC. With a clinically relevant cutoff, 41.7% of the TMA samples were PD-L1 positive. PD-L1 level was much lower in EGFR-mutant patients and seemed to be a favorable prognostic factor for both overall survival (OS) and recurrence-free survival (RFS). These findings were confirmed in the whole-section samples except that their survival data were not mature enough for correlation analysis. In summary, PD-L1 expression was detected in approximately 40% of PTEN-qualified Chinese NSCLC samples, negatively correlated with EGFR mutation and seemed to be a favorable prognostic factor for both OS and RFS. Notably, the different results from PTEN-qualified and PTEN-disqualified samples underscore the importance of tissue quality control prior to biomarker testing.
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Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Mutação , PTEN Fosfo-Hidrolase/genética , Análise Serial de Tecidos/normas , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Estudos de Coortes , Detecção Precoce de Câncer , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de SobrevidaRESUMO
BACKGROUND: Lipotoxicity plays an important role in the pathogenesis of kidney injury. Our previous study demonstrated that activation of local renin-angiotensin system (RAS) was involved in saturated free fatty acids palmitic acid (PA)-induced tubular cell injuries. The current study aims to investigate whether suppression of RAS by combination of direct renin inhibitor aliskiren and noncanonical RAS pathway chymase inhibitor chymostatin attenuates PA or cholesterol induced-endoplasmic reticulum stress (ER stress) and apopotosis in cultured human proximal tubular HK2 cells. METHODS: HK2 cells were treated with saturated fatty acid PA (0.6 mM) for 24 h or cholesterol (10 µg/ml) for 6d with or without chymostatin and/or aliskiren. Expressions of the ER stress associated proteins and apoptosis markers were detected by western blotting. The mRNA levels of RAS components were measured by real-time qPCR. RESULTS: Combination treatment of chymostatin and aliskiren markedly suppressed PA or cholesterol-induced ER stress, as reflected by increased BiP, IRE1α, phosphorylated-eIF2α and ATF4 as well as proapoptotic transcription factor CHOP. The ratio of Bax/Bcl-2 and cleaved caspase-3, two markers of apoptosis were upregulated by PA or cholesterol treatment. PA treatment was also associated with increased levels of angiotensinogen and angiotensin type 1 receptor (AT1R) mRNA expression. Combination treatment of chymostatin and aliskiren markedly suppressed PA or cholesterol-induced ER stress and apoptosis. The protective effect of two inhibitors was also observed in primary cultured cortical tubular cells treated with PA. In contrast, chymostatin and/or aliskiren failed to prevent ER stress induced by tunicamycin. CONCLUSIONS: These results suggested that combination treatment of chymostatin and aliskiren attenuates lipid-induced renal tubular cell injury, likely through suppressing activation of intracellular RAS.
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Amidas/farmacologia , Anti-Hipertensivos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Fumaratos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Oligopeptídeos/farmacologia , Inibidores de Serina Proteinase/farmacologia , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Transformada , Colesterol/farmacologia , Combinação de Medicamentos , Sinergismo Farmacológico , Chaperona BiP do Retículo Endoplasmático , Endorribonucleases/genética , Endorribonucleases/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Ácido Palmítico/antagonistas & inibidores , Ácido Palmítico/farmacologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Transdução de Sinais , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismoRESUMO
The direct renin inhibitor aliskiren has been shown to be retained and persist in medullary collecting ducts even after treatment is discontinued, suggesting a new mechanism of action for this drug. The purpose of the present study was to investigate whether aliskiren regulates renal aquaporin expression in the collecting ducts and improves urinary concentrating defect induced by lithium in mice. The mice were fed with either normal chow or LiCl diet (40 mmol·kg dry food-1·day-1 for 4 days and 20 mmol·kg dry food-1·day-1 for the last 3 days) for 7 days. Some mice were intraperitoneally injected with aliskiren (50 mg·kg body wt-1·day-1 in saline). Aliskiren significantly increased protein abundance of aquaporin-2 (AQP2) in the kidney inner medulla in mice. In inner medulla collecting duct cell suspension, aliskiren markedly increased AQP2 and phosphorylated AQP2 at serine 256 (pS256-AQP2) protein abundance, which was significantly inhibited both by adenylyl cyclase inhibitor MDL-12330A and by PKA inhibitor H89, indicating an involvement of the cAMP-PKA signaling pathway in aliskiren-induced increased AQP2 expression. Aliskiren treatment improved urinary concentrating defect in lithium-treated mice and partially prevented the decrease of AQP2 and pS256-AQP2 protein abundance in the inner medulla of the kidney. In conclusion, the direct renin inhibitor aliskiren upregulates AQP2 protein expression in inner medullary collecting duct principal cells and prevents lithium-induced nephrogenic diabetes insipidus likely via cAMP-PKA pathways.
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Amidas/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Aquaporina 2/metabolismo , Diabetes Insípido Nefrogênico/tratamento farmacológico , Fumaratos/uso terapêutico , Túbulos Renais Coletores/efeitos dos fármacos , Amidas/farmacologia , Angiotensina II/urina , Animais , Anti-Hipertensivos/farmacologia , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Avaliação Pré-Clínica de Medicamentos , Fumaratos/farmacologia , Medula Renal/metabolismo , Túbulos Renais Coletores/metabolismo , Lítio , Masculino , Camundongos Endogâmicos C57BL , Poliúria/induzido quimicamente , Poliúria/tratamento farmacológico , Receptores de Superfície Celular/metabolismo , Receptor de Pró-ReninaRESUMO
One-dimensional wires constitute a fundamental building block in nanoscale electronics. However, truly one-dimensional metallic wires do not exist due to Peierls distortion. Molecular wires come close to being stable one-dimensional wires, but are typically semiconductors, with charge transport occurring via tunneling or thermally-activated hopping. In this review, we discuss electron transport through molecular wires, from a theoretical, quantum mechanical perspective based on first principles. We focus specifically on the off-resonant tunneling regime, applicable to shorter molecular wires (<â¼4-5 nm) where quantum mechanics dictates electron transport. Here, conductance decays exponentially with the wire length, with an exponential decay constant, beta, that is independent of temperature. Different levels of first principles theory are discussed, starting with the computational workhorse - density functional theory (DFT), and moving on to many-electron GW methods as well as GW-inspired DFT + Sigma calculations. These different levels of theory are applied in two major computational frameworks - complex band structure (CBS) calculations to estimate the tunneling decay constant, beta, and Landauer-Buttiker transport calculations that consider explicitly the effects of contact geometry, and compute the transmission spectra directly. In general, for the same level of theory, the Landauer-Buttiker calculations give more quantitative values of beta than the CBS calculations. However, the CBS calculations have a long history and are particularly useful for quick estimates of beta. Comparing different levels of theory, it is clear that GW and DFT + Sigma calculations give significantly improved agreement with experiment compared to DFT, especially for the conductance values. Quantitative agreement can also be obtained for the Seebeck coefficient - another independent probe of electron transport. This excellent agreement provides confirmative evidence of off-resonant tunneling in the systems under investigation. Calculations show that the tunneling decay constant beta is a robust quantity that does not depend on details of the contact geometry, provided that the same contact geometry is used for all molecular lengths considered. However, because conductance is sensitive to contact geometry, values of beta obtained by considering conductance values where the contact geometry is changing with the molecular junction length can be quite different. Experimentally measured values of beta in general compare well with beta obtained using DFT + Sigma and GW transport calculations, while discrepancies can be attributed to changes in the experimental contact geometries with molecular length. This review also summarizes experimental and theoretical efforts towards finding perfect molecular wires with high conductance and small beta values.
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Introduction: The relationship of exostosin 1 and exostosin 2 (EXT1/EXT2) expression and outcomes in membranous lupus nephritis (MLN) was controversial. Methods: EXT1/EXT2 was performed by immunohistochemistry (IHC) in 283 consecutive patients with MLN. Clinicopathological characteristics and outcomes of EXT1/EXT2-positive patients were compared with EXT1/EXT2-negative patients. The primary end points were adverse renal events, including death, dialysis, and renal transplantation. Results: Of the patients with MLN, 29.3% were positive for EXT1/EXT2. The prevalence of EXT1/2-positive MLN was significantly higher in pure class V MLN than those for mixed class V MLN (44.2% vs. 19.4%, P < 0.001). For EXT1/EXT2-positive patients, the median time between onset of lupus and renal biopsy, and lupus nephritis and renal biopsy is shorter (6 [interquartile range, IQR: 2-25] months vs. 12 [IQR: 3-49] months, P = 0.008 and 3 [IQR: 2-18] months vs. 6 [IQR: 2-23] months, P = 0.039) and they had significantly lower systemic lupus erythematosus Disease Activity Index (SLEDAI) scores (P = 0.015) and lower serum creatinine levels (P < 0.001), higher hemoglobin (P = 0.006) as well as lower blood pressure. The EXT1/EXT2-positive patients had significantly fewer chronicity features (glomerulosclerosis, P < 0.001; interstitial fibrosis, P = 0.006; and tubular atrophy, P = 0.002) and fewer activity indicators (endocapillary hypercellularity, P = 0.012; cellular crescents, P = 0.007; and fibrocellular crescents, P < 0.001) on renal biopsy. After a median follow-up of 65 (28-126) months, EXT1/EXT2-positive patients were less likely to experience adverse renal events (2.4% vs. 16.0%, P = 0.001). Conclusion: Compared with EXT1/EXT2-negative patients, the EXT1/EXT2-positive patients presented with lower disease activity and were less likely to experience adverse renal events in relationship with the chronicity index.
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Objective: The currently established diagnostic and prognostic tools for diabetic kidney disease (DKD) have limitations, which demands the necessity to find new genes and pathways associated with diagnosis and treatment. Our study aims to reveal the gene expression alteration and discover critical genes involved in the development of DKD, thus providing novel diagnostic molecular markers and therapeutic targets. Materials and methods: The differences of infiltrating immune cells within kidney were compared between healthy living donors and DKD patients. Besides, differentially expressed genes (DEGs) within kidney from healthy living donor, early stage DKD and advanced stage DKD samples were detected. Furthermore, the weighted co-expressed network (WGCNA) and protein-protein interaction (PPI) network were constructed, followed by recognition of core hub genes and module analysis. Receiver operating characteristic (ROC) curve analysis was implemented to determine the diagnostic value of hub genes, correlation analysis was employed to explore the association between hub genes and infiltrating immune cells, and certain hub genes was validated by quantitative real-time PCR and immunohistochemistry staining in cultured tubule cells and diabetic mice kidney. Finally, the candidate small molecules as potential drugs to treat DKD were anticipated through utilizing virtual screening and molecular docking investigation. Results: Our study revealed significantly higher proportion of infiltrating immune cells within kidney from DKD patients via probing the immune landscape by single-cell transcriptomics. Besides, 126 commonly shared DEGs identified among three group samples were enriched in immune biological process. In addition, the ROC curve analysis demonstrated the strong diagnostic accuracy of recognized hub genes (NFKB1, DYRK2, ATAD2, YAP1, and CHD3) from PPI network. Correlation analysis further confirmed the positive association between these hub genes with infiltrating natural killer cells. More importantly, the mRNA transcripts and protein abundance of YAP1 were significantly higher in high glucose-treated renal tubule cells and diabetic mice kidney, and the small molecules exhibiting the best binding affinities with YAP1 were predicted and acquired. Conclusion: Our findings for the first time indicate that NFKB1, DYRK2, ATAD2, YAP1, and CHD3 might be potential novel biomarkers and therapeutic targets for DKD, providing insights into the molecular mechanisms underlying the pathogenesis of DKD.
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Objective: The commonalities and differences regarding immune states between glomerular and tubulointerstitial compartments of IgA nephropathy (IgAN) remains largely undetermined. We aim to perform bioinformatic analysis for providing a comprehensive insight into the characteristics of immune cells and associated molecular mechanisms in IgAN. Materials and Methods: We performed integrated bioinformatic analyses by using IgAN-related datasets from the Gene Expression Omnibus database. First, the differentially expressed genes (DEGs) were identified and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Then, CIBERSORT was employed to determine the landscape of infiltrating immune cells in both glomerular and tubulointerstitial compartments of IgAN patients, followed by Pearson's correlation analysis and principal component analysis (PCA). Finally, commonly shared DEGs between glomerular and tubulointerstitial entities were recognized, followed by correlation analyses to identify the dominant commonly shared DEGs associated with immune cell infiltration in IgAN. Results: GO and KEGG enrichment analyses showed apparently distinct biological processes in the glomerular and tubulointerstitial compartments of IgAN. In addition, CIBERSORT analyses revealed a clear trend of increasing proportions of M1 macrophage and M2 macrophage in the glomerular compartment while noticeably higher proportions of resting CD4+ memory T cells and M2 macrophages in the tubulointerstitial compartments. The PCA analyses showed that the varying composition of immune cells in both glomerular and tubulointerstitial entities was compelling to distinguish IgAN patients from healthy living controls. In addition, 21 commonly shared DEGs between glomerular and tubulointerstitial entities were recognized as key regulators in the pathogenesis of IgAN, among which the enhanced hemoglobin subunit beta (HBB) gene expression was found to be positively associated with M2 macrophage in the glomerular compartment and resting CD4+ memory T cells in the tubulointerstitial compartment. Most importantly, FBJ murine osteosarcoma viral oncogene homolog B (FOSB) gene deficiency was recognized as the dominant alteration in promoting M2 macrophage infiltration in the glomerular compartment of IgAN. Conclusion: The findings from our current study for the first time reveal commonalities and differences regarding immune states between glomerular and tubulointerstitial compartments, as well as decode the essential role of M2 macrophages and associated molecular patterns within the microenvironments of IgAN.
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Calcium is one of the most abundant and cheapest elements on earth. However, due to the lack of d-orbitals for chemical adsorption, it is generally considered as a stoichiometric reagent with no catalytic activities in heterogeneous catalysis. In this research, we have revealed that atomically confined Ca in nitrogen-doped graphene (Ca1-NG) can be an effective heterogeneous catalyst to boost both electrocatalytic and photocatalytic hydrogen evolution reactions (HER). Ca single atoms anchored in NG can efficiently enhance the HER performance due to the improvement of the interfacial charge transfer rate and suppression of the photo-generated charge recombination. Density functional theory calculations show that the high catalytic activity of Ca1-NG results from the Ca single atoms in NG, which leads to multiple H adsorption configurations with favorable ΔGH∗ values for HER. This research can be valuable for the designing of environmentally friendly, economical and efficient catalysts for renewable hydrogen production.
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Obesity-related kidney diseases are becoming serious health problems worldwide, yet the mechanism by which obesity causes kidney injury is not fully understood. The purpose of current study was to investigate the role of Mas receptor in lipid-induced kidney injury. In mice fed with high-fat diet (HFD), the protein abundance of markers of autophagy, endoplasmic reticulum stress (ER stress) and apoptosis was dramatically increased in the kidney cortex, which was markedly prevented by Mas deletion (Mas-/-) or Mas receptor antagonist A779. Palmitic acid (PA) induced persistently increased autophagy, ER stress, and apoptosis as well as mitochondrial injuries in primary cultured proximal tubular cells from wild type, but not from Mas-/- mice. In human proximal tubular HK2 cells, PA-induced autophagy and ER stress was aggravated by Mas agonists Ang (1-7) or AVE0991, but attenuated by A779 or Mas knockdown. Stimulation of Mas resulted in elevated intracellular calcium levels [Ca2+]i in HK2 cells treated with PA, whereas inhibition or knockdown of Mas decreased [Ca2+]i. Mitochondrial outer membrane located voltage-dependent anion channel (VDAC1) was markedly upregulated in HK2 cells treated with PA, which was associated with impaired mitochondrial morphology and depolarization. These were enhanced by AVE0991 and suppressed by A779 or Mas knockdown. Mas knockdown in HK2 cells prevented impaired interactions among VDAC1, autophagy adaptor P62, and ubiquitin, induced by PA, leading to a potential ubiquitination of VDAC1. In conclusion, Mas receptor-mediated lipid-induced impaired autophagy and ER stress in the kidney, likely contributing to tubular injuries in obesity-related kidney diseases.
Assuntos
Nefropatias/metabolismo , Obesidade/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Angiotensina II/análogos & derivados , Angiotensina II/farmacologia , Animais , Autofagia/fisiologia , Linhagem Celular , Dieta Hiperlipídica , Estresse do Retículo Endoplasmático , Humanos , Nefropatias/genética , Nefropatias/patologia , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Fragmentos de Peptídeos/farmacologia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Acoplados a Proteínas G/antagonistas & inibidoresRESUMO
OBJECTIVE: To explore predictive value of endometrial receptivity and pregnancy outcome by hysteroscopy examination at the phase of implantation window in unexplained infertile women. METHODS: From Oct. 2007 to Mar. 2009, 93 unexplained infertile women underwent hysteroscopy examination at 7 approximately 9 days after a spontaneous ovulation in Family Planning Research Institute of Guangdong Province. According to the endometrial glandular openings and vascular shape, 79 cases without pathological endometrial changes were divided into 60 cases in good endometrium group and 19 cases in poor endometrium group. The following clinical parameters were analyzed and compared between two groups, including endometrial configuration, thickness, secretion, the development and number of pinopodes, vascular distribution, and the level of sex hormone, leukemia inhibitory factor (LIF) and glycodelin in the uterine flushing, and pregnancy outcome. RESULTS: (1) There was no statistical difference in the level of serum estrogen and progesterone at the phase of implantation window, which were (518 +/- 176) pmol/L, (40 +/- 20) nmol/L in good group and (513 +/- 244) pmol/L, (37 +/- 19) nmol/L in poor group (P < 0.05). The endometrium thickness at periovulatroy and implantation window days (1.06 +/- 0.10) cm/(1.16 +/- 0.08) cm in good group did not show significant difference with (0.93 +/- 0.12) cm/(1.02 +/- 0.10) cm in poor group (P > 0.05). The proportion of type A, B and C endometrium at periovulatory days were 63% (12/19), 37% (7/19) and 0 (0/19) in good group and 23% (14/60), 77% (46/60) and 0 (0/60) in poor group. When compared with those of type A or B between two groups respectively, it all showed statistical difference (P < 0.05). However, at phase of implantation window, endometrium configurations were all type B at both groups. (2) 90% (17/19) of women in good group and 7% (4/60) of women in poor group showed normal endometrial secretion function, which showed significant differences (P < 0.01). (3) The percentage of fully developed pinopodes and abundant pinopodes [84% (16/19) and 90% (17/19)] in good group were significantly higher than 42% (25/60) and 57% (34/60) in poor group (P < 0.05). (4) The level of CD(34) expression and microvessel density [MVD; (40.1 +/- 1.2) positive unit (PU) and (21.7 +/- 4.0)/high power field (HP)] in good group were significantly higher than (18.1 +/- 1.3) PU and (8.5 +/- 1.3)/HP in poor group (P < 0.01). (5) The level of LIF and glycodelin in uterine flushing [(72 +/- 54) ng/L and (196 +/- 20) microg/L] in good group were significantly higher than (15 +/- 16) ng/L and (116 +/- 26) microg/L in poor group (P < 0.05). (6) The rate of clinical pregnancy, spontaneous abortion and term delivery were 74% (14/19), 0 (0/14) and 100% (14/14) in good group and 23% (14/60), 14% (2/14) and 86% (12/14) in poor group, the rate of clinical pregnancy and term delivery in good group were significantly increased when compared with those in poor group (P < 0.01). CONCLUSIONS: Hysteroscopy examination at the phase of implantation window could reflect the development of glandular openings and vasculature. It is a preferable method to evaluate the endometrial receptivity and predict pregnancy outcome.
Assuntos
Endométrio/diagnóstico por imagem , Endométrio/fisiologia , Histeroscopia , Infertilidade Feminina , Resultado da Gravidez , Adulto , Capilares , Endométrio/irrigação sanguínea , Estradiol/sangue , Feminino , Humanos , Fator Inibidor de Leucemia/metabolismo , Fase Luteal , Microscopia Eletrônica/métodos , Valor Preditivo dos Testes , Gravidez , Progesterona/sangue , Sensibilidade e Especificidade , UltrassonografiaRESUMO
Water can diffuse freely through the lipid bilayer at a limited rate or by water channel proteins in a rapid speed. Aquaporins (AQPs) are a family of membrane water channel proteins that mainly function as regulators of intracellular and intercellular water flow. They are distributed wildly in specific cell types in multiple organs and tissues. Since the first AQP was identified, 13 AQPs have been characterized in mammals. Structural analysis shows that AQPs are homotetramers with each AQP monomer containing six transmembrane α-helices, two half helices and five connecting loops with two conserved asparagine-proline-alanine (NPA) motifs embedding into the plasma membrane. AQPs are demonstrated to selectively transport water but also some other small molecules. The cellular functions of aquaporins are regulated mainly by posttranslational modifications, e.g., phosphorylation, ubiquitination, glycosylation, subcellular distribution, degradation, and protein interactions. Aquaporins, in particular, AQP2 plays an important role in some disease conditions such as water loss and gain. Insights into the molecular mechanisms regulating AQPs and its clinical significance are proving to be fundamental for development of novel therapeutic targets or reliable diagnostic and prognostic biomarkers. In this chapter, we summarize the molecular aspects of aquaporins which include the isoforms, crystal structure and the molecular mechanisms underlying the regulation of AQPs, with most focus on arginine vasopressin-regulated AQP2.
Assuntos
Aquaporinas/química , Aquaporinas/metabolismo , Humanos , Fosforilação , Estrutura Secundária de ProteínaRESUMO
Background: Chronic kidney diseases (CKD) are usually associated with dyslipidemia. Statin therapy has been primarily recommended for the prevention of cardiovascular risk in patients with CKD; however, the effects of statins on kidney disease progression remain controversial. This study aims to investigate the effects of statin treatment on renal handling of water in patients and in animals on a high-fat diet. Methods: Retrospective cohort patient data were reviewed and the protein expression levels of aquaporin-2 (AQP2) and NLRP3 inflammasome adaptor ASC were examined in kidney biopsy specimens. The effects of statins on AQP2 and NLRP3 inflammasome components were examined in nlrp3-/- mice, 5/6 nephroectomized (5/6Nx) rats with a high-fat diet (HFD), and in vitro. Results: In the retrospective cohort study, serum cholesterol was negatively correlated to eGFR and AQP2 protein expression in the kidney biopsy specimens. Statins exhibited no effect on eGFR but abolished the negative correlation between cholesterol and AQP2 expression. Whilst nlrp3+/+ mice showed an increased urine output and a decreased expression of AQP2 protein after a HFD, which was moderately attenuated in nlrp3 deletion mice with HFD. In 5/6Nx rats on a HFD, atorvastatin markedly decreased the urine output and upregulated the protein expression of AQP2. Cholesterol stimulated the protein expression of NLRP3 inflammasome components ASC, caspase-1 and IL-1ß, and decreased AQP2 protein abundance in vitro, which was markedly prevented by statins, likely through the enhancement of ASC speck degradation via autophagy. Conclusion: Serum cholesterol level has a negative correlation with AQP2 protein expression in the kidney biopsy specimens of patients. Statins can ameliorate cholesterol-induced inflammation by promoting the degradation of ASC speck, and improve the expression of aquaporin in the kidneys of animals on a HFD.
Assuntos
Aquaporina 2/análise , Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Rim/efeitos dos fármacos , Insuficiência Renal Crônica/tratamento farmacológico , Adulto , Animais , Aquaporina 2/metabolismo , Biópsia , Colesterol/sangue , Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Progressão da Doença , Dislipidemias/sangue , Dislipidemias/complicações , Dislipidemias/imunologia , Feminino , Taxa de Filtração Glomerular , Humanos , Inflamassomos/antagonistas & inibidores , Inflamassomos/imunologia , Inflamassomos/metabolismo , Rim/imunologia , Rim/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/imunologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/imunologia , Estudos RetrospectivosRESUMO
An introduction of the design, features and contraceptive principle of an oviduct contraceptive plug is given in this paper. The plug is made of polyethylene, based on the oviductal morphology. It can be introduced and removed by a hysteroscope and is expected to be a transcervical, implantable and permanent intratubal contraceptive device.
Assuntos
Dispositivos Anticoncepcionais Femininos , Polietileno , Esterilização Tubária/instrumentação , Desenho de EquipamentoRESUMO
Immunotherapeutic agents have demonstrated encouraging signs of clinical utility in non-Hodgkin lymphoma. The goal of this study is to analyze the immune characteristics of Chinese patients with diffuse large B-cell lymphoma (DLBCL) to inform the development of immunotherapies in this patient population. Tumor samples from 211 DLBCL patients were analyzed for cell of origin (COO) and immune characteristics using the NanoString platform as well as MYC protein expression through immunohistochemistry. Lower incidence of the germinal center B-cell (GCB) subtype (93/211, 44.1%) was observed in this cohort. Compared to the GCB subtype, the activated B-cell (ABC) subtype was associated with significantly increased expression of multiple pro-inflammatory gene signatures and decreased expression of anti-inflammatory gene signatures. Instead of affecting the pro-inflammatory genes, MYC protein overexpression showed a negative correlation with the expression of T-cell receptor (TCR) and T regulatory genes as well as the OX40 gene. Regardless of COO, higher PD-L1 or IDO1 gene expression correlated with increased expression of T effector and Interferon-γ gene signatures while the expression of multiple oncogenes including ACTR3B, ERBB2, AKT2 and SMARCD1 was down-regulated. Our findings may thus be helpful in guiding further development of immunotherapies for the different subsets of Chinese DLBCL patients.