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In this study, the transcriptome profiles of tissue-cultured grapevine (Vitis vinifera L. × Vitis labrusca L.: Rose Honey) seedlings inoculated with fungal endophytes Epicoccum layuense R2-21 (Epi R2-21) and Alternaria alternata XHYN2 (Alt XHYN2), were analyzed at three different time points (6 h, 6 d, and 15 d). A total of 4783 differentially expressed genes (DEGs) was found, of which 1853 (6 h), 3878 (6 d), and 4732 (15 d) were differentially expressed relative to those of the control in endophyte Epi R2-21 treatments, while a total of 5898 DEGs, of which 2726 (6 h), 4610 (6 d), and 3938 (15 d) were differentially expressed in endophyte Alt XHYN2 treatments. DEGs enriched in secondary metabolic pathways, plant-pathogen interaction, and hormone signalling were further analysed. The upregulated DEGs in the Epi R2-21 and Alt XHYN2 treatments, both enriched in the Kyoto Encyclopedia of Genes and Genomes (KEGG), were mainly involved in flavonoid biosynthesis, phenylpropanoid biosynthesis, stilbenoid, diarylheptanoid and gingerol biosynthesis, phenylalanine metabolism, and circadian rhythms-plant and plant-pathogen interactions, similar to the trend observed in our previous study conducted on the cultivar 'Cabernet Sauvignon' (Vitis vinifera L.). Taken together with the results obtained from the cultivar 'Cabernet Sauvignon', it was found that tissue-cultured seedlings of the cultivar 'Rose Honey' induced a stronger defence response to fungal endophyte infection than that of the cultivar 'Cabernet Sauvignon', and inoculation with the endophyte Alt XHYN2 triggered a stronger response than inoculation with the endophyte Epi R2-21. In addition, the protein-protein interaction (PPI) network revealed that the genes VIT_16s0100g00910, encoding CHS, and VIT_11s0065g00350, encoding CYP73A, were involved in secondary metabolism and thus mediated in the resistance mechanism of grapevine on both the cultivars. The results showed that inoculation with the endophytes Epi R2-21 and Alt XHYN2 had a great ability to induce defence responses and reprogram the gene expression profiles in different grapevine cultivars, which deepens our knowledge of the interaction between fungal endophytes and grapevine and gives hints for grape quality management in viticulture using candidate fungal endophytes.
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Background: This study investigates the link between genetic variants associated with kidney function and immunoglobulin A (IgA) nephropathy (IgAN) progression. Methods: We recruited 961 biopsy-proven IgAN patients and 651 non-IgAN end-stage renal disease (ESRD) patients from Ruijin Hospital. Clinical and renal pathological data were collected. The primary outcome was the time to ESRD. A healthy population was defined as estimated glomerular filtration rate >60 mL/min/1.73 m2 without albuminuria or hematuria. Fifteen single-nucleotide polymorphisms (SNPs) were selected from a genome-wide association study of kidney function and genotyped by the SNaPshot. Immunohistochemistry in renal tissue and ELISA in urine samples were performed to explore the potential functions of genetic variations. Results: The rs77924615-G was independently associated with an increased risk for ESRD in IgAN patients after adjustments for clinical and pathologic indices, and treatment (adjusted hazard ratio 2.10; 95% confidence interval 1.14-3.88). No significant differences in ESRD-free survival time were found among different genotypes in non-IgAN ESRD patients (log-rank, P = .480). Moreover, rs77924615 exhibited allele-specific enhancer activity by dual-luciferase reporter assay. Accordingly, the urinary uromodulin-creatinine ratio (uUCR) was significantly higher in healthy individuals with rs77924615 AG or GG than in individuals with AA. Furthermore, uromodulin expression in tubular epithelial cells was higher in patients with rs77924615 AG or GG. Finally, we confirmed that an increased uUCR (P = .009) was associated with faster IgAN progression. Conclusion: The SNP rs77924615, which modulates the enhancer activity of the UMOD gene, is associated with renal function deterioration in IgAN patients by increasing uromodulin levels in both the renal tubular epithelium and urine.
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COL4A3/A4/A5 mutations have been identified as critical causes of Alport syndrome and other genetic chronic kidney diseases. However, the underlying pathogenesis remains unclear, and specific treatments are lacking. Here, we constructed a transgenic Alport syndrome mouse model by generating a mutation (Col4a3 p.G799R) identified previously from one large Alport syndrome family into mice. We observed that the mutation caused a pathological decrease in intracellular and secreted collagen IV α3α4α5 heterotrimers. The mutant collagen IV α3 chains abnormally accumulated in the endoplasmic reticulum and exhibited defective secretion, leading to persistent endoplasmic reticulum stress in vivo and in vitro. RNA-seq analysis revealed that the MyD88/p38 MAPK pathway plays key roles in mediating subsequent inflammation and apoptosis signaling activation. Treatment with tauroursodeoxycholic acid, a chemical chaperone drug that functions as an endoplasmic reticulum stress inhibitor, effectively suppressed endoplasmic reticulum stress, promoted secretion of the α3 chains, and inhibited the activation of the MyD88/p38 MAPK pathway. Tauroursodeoxycholic acid treatment significantly improved kidney function in vivo. These results partly clarified the pathogenesis of kidney injuries associated with Alport syndrome, especially in glomeruli, and suggested that tauroursodeoxycholic acid might be useful for the early clinical treatment of Alport syndrome.
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Colágeno Tipo IV , Estresse do Retículo Endoplasmático , Mutação , Nefrite Hereditária , Ácido Tauroquenodesoxicólico , Proteínas Quinases p38 Ativadas por Mitógeno , Animais , Humanos , Masculino , Camundongos , Apoptose/efeitos dos fármacos , Autoantígenos/genética , Autoantígenos/metabolismo , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Rim/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Nefrite Hereditária/genética , Nefrite Hereditária/tratamento farmacológico , Nefrite Hereditária/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ácido Tauroquenodesoxicólico/farmacologia , Ácido Tauroquenodesoxicólico/uso terapêuticoRESUMO
BACKGROUND: Kidney damage is common in patients with Fabry disease (FD), but more accurate information about the risk of progression to kidney failure is needed for clinical decision-making. In particular, FD patients with mild renal involvement often lack timely intervention and treatment. We aimed to utilize a model to predict the risk of renal progression in FD patients. METHODS: Between November 2011 and November 2019, ERT-naive patients with FD were recruited from three medical centers in China. To assess the risk of a 50% decline in the estimated glomerular filtration rate (eGFR) or end-stage kidney disease (ESKD), Cox proportional hazards models were utilized. The performance of these models was assessed using discrimination, calibration, and reclassification. RESULTS: A total of 117 individuals were enrolled. The mean follow-up time was 4.8 years, during which 35 patients (29.9 %) progressed to the composite renal outcomes. Male sex, baseline proteinuria, eGFR and globotriaosylsphingosine (Lyso-Gb3) were found to be independent risk factors for kidney progression by the Cox model, based on which a combined model containing those clinical variables and Lyso-Gb3 and clinical models including only clinical indicators were constructed. The two prediction models had relatively good performance, with similar model fit measured by R2 (59.8 % vs. 61.1 %) and AIC (51.54 vs. 50.08) and a slight increase in the C statistic (0.949 vs. 0.951). Calibration curves indicated closer alignment between predicted and actual renal outcomes in the combined model. Furthermore, subgroup analysis revealed that Lyso-Gb3 significantly improved the predictive performance of the combined model for kidney prognosis in low-risk patients with a baseline eGFR over 60 ml/min/1.73 m2 or proteinuria levels less than 1 g/d when compared to the clinical model. CONCLUSIONS: Lyso-Gb3 improves the prediction of kidney outcomes in FD patients with a low risk of progression, suggesting that these patients may benefit from early intervention to assist in clinical management. These findings need to be externally validated.
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Doença de Fabry , Humanos , Masculino , Doença de Fabry/tratamento farmacológico , alfa-Galactosidase , Rim , Esfingolipídeos , Proteinúria , Glicolipídeos , Medição de Risco , Progressão da DoençaRESUMO
INTRODUCTION: The aim of this study was to test whether a combined risk score on the basis of genetic risk and serology can improve the prediction of kidney failure in phospholipase A2 receptor (PLA2R)-associated primary membranous nephropathy. METHODS: We performed a retrospective analysis of 519 biopsy-proven PLA2R-associated primary membranous nephropathy patients with baseline eGFR ≥25 ml/min per 1.73 m 2 . The combined risk score was calculated by combining the genetic risk score with PLA2R ELISA antibody titers. The primary end point was kidney disease progression defined as a 50% reduction in eGFR or kidney failure. Cox proportional hazard regression analysis and C-statistics were applied to compare the performance of PLA2R antibody, genetic risk score, and combined risk score, as compared with clinical factors alone, in predicting primary outcomes. RESULTS: The median age was 56 years (range, 15-82 years); the male-to-female ratio was 1:0.6, the median eGFR at biopsy was 99 ml/min per 1.73 m 2 (range: 26-167 ml/min per 1.73 m 2 ), and the median proteinuria was 5.3 g/24 hours (range: 1.5-25.8 g/24 hours). During a median follow-up of 67 (5-200) months, 66 (13%) had kidney disease progression. In Cox proportional hazard regression models, PLA2R antibody titers, genetic risk score, and combined risk score were all individually associated with kidney disease progression with and without adjustments for age, sex, proteinuria, eGFR, and tubulointerstitial lesions. The best-performing clinical model to predict kidney disease progression included age, eGFR, proteinuria, serum albumin, diabetes, and tubulointerstitial lesions (C-statistic 0.76 [0.69-0.82], adjusted R 2 0.51). Although the addition of PLA2R antibody titer improved the performance of this model (C-statistic: 0.78 [0.72-0.84], adjusted R 2 0.61), replacing PLA2R antibody with the combined risk score improved the model further (C-statistic: 0.82 [0.77-0.87], adjusted R 2 0.69, difference of C-statistics with clinical model=0.06 [0.03-0.10], P < 0.001; difference of C-statistics with clinical-serologic model=0.04 [0.01-0.06], P < 0.001). CONCLUSIONS: In patients with PLA2R-associated membranous nephropathy, the combined risk score incorporating inherited risk alleles and PLA2R antibody enhanced the prediction of kidney disease progression compared with PLA2R serology and clinical factors alone.
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Progressão da Doença , Taxa de Filtração Glomerular , Glomerulonefrite Membranosa , Receptores da Fosfolipase A2 , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Autoanticorpos/sangue , Estratificação de Risco Genético , Glomerulonefrite Membranosa/genética , Glomerulonefrite Membranosa/imunologia , Glomerulonefrite Membranosa/sangue , Valor Preditivo dos Testes , Prognóstico , Receptores da Fosfolipase A2/imunologia , Receptores da Fosfolipase A2/genética , Estudos Retrospectivos , Medição de RiscoRESUMO
BACKGROUND: Lung cancer is a highly prevalent malignancy worldwide and is associated with high mortality rates. While the involvement of endoplasmic reticulum (ER) stress in the development of lung adenocarcinoma (LUAD) has been established, the underlying mechanism remains unclear. METHODS: In this study, we utilized data from The Cancer Genome Atlas (TCGA) to identify differentially expressed endoplasmic reticulum stress-related genes (ERSRGs) between LUAD and normal tissues. We performed various bioinformatics analyses to investigate the biological functions of these ERSRGs. Using LASSO analysis and multivariate stepwise regression, we constructed a novel prognostic model based on the ERSRGs. We further validated the performance of the model using two independent datasets from the Gene Expression Omnibus (GEO). Additionally, we conducted functional enrichment analysis, immune checkpoint analysis, and immune infiltration analysis and drug sensitivity analysis of LUAD patients to explore the potential biological function of the model. Furthermore, we conducted a battery of experiments to verify the expression of ERSRGs in a real-world cohort. RESULTS: We identified 106 ERSRGs associated with LUAD, which allowed us to classify LUAD patients into two subtypes based on gene expression differences. Using six prognostic genes (NUPR1, RHBDD2, VCP, BAK1, EIF2AK3, MBTPS2), we constructed a prognostic model that exhibited excellent predictive performance in the training dataset and was successfully validated in two independent external datasets. The risk score derived from this model emerged as an independent prognostic factor for LUAD. Confirmation of the linkage between this risk model and immune infiltration was affirmed through the utilization of Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The q-PCR results verified significant differences in the expression of prognostic genes between cancer and paracancer tissues. Notably, the protein expression of NUPR1, as determined by immunohistochemistry (IHC), exhibited an opposite pattern compared to the mRNA expression patterns. CONCLUSION: This study establishes a novel prognostic model for LUAD based on six ER stress-related genes, facilitating the prediction of LUAD prognosis. Additionally, NUPR1 was identified as a potential regulator of stress in LUAD.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Multiômica , Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética , Biologia Computacional , Estresse do Retículo Endoplasmático , Prognóstico , Proteínas de MembranaRESUMO
In this study, we focused on grapevine-endophyte interactions and reprogrammed secondary metabolism in the host plant due to defense against the colonization of endophytes. Thus, the transcriptional responses of tissue cultured grapevine seedlings (Vitis vinifera L. cv.: Cabernet Sauvignon) to two fungal endophytes Epicoccum layuense R2-21 (Epi R2-21) and Alternaria alternata XHYN2 (Alt XHYN2) at three different time points (6 h, 6 d, 15 d) were analyzed. As expected, a total of 5748 and 5817 differentially expressed genes (DEGs) were separately initiated in Epi R2-21 and Alt XHYN2 symbiotic tissue cultured seedlings compared to no endophyte treatment. The up-regulated DEGs at all time points in Epi R2-21- or Alt XHYN2-treated seedlings were mainly enriched in the flavonoid biosynthesis, phenylpropanoid biosynthesis, phenylalanine metabolism, stilbenoid, diarylheptanoid and gingerol biosynthesis, and circadian rhythm-plant pathways. In addition, the up-regulated DEGs at all sampling times in Alt XHYN2-treated tissue cultured seedlings were enriched in the plant-pathogen interaction pathway, but appeared in Epi R2-21 symbiotic seedlings only after 15 d of treatment. The down-regulated DEGs were not enriched in any KEGG pathways after 6 h inoculation for Epi R2-21 and Alt XHYN2 treatments, but were enriched mainly in photosynthesis-antenna proteins and plant hormone signal transduction pathways at other sampling times. At three different time points, a total of 51 DEGs (all up-regulated, 1.33-10.41-fold) were involved in secondary metabolism, and 22 DEGs (all up-regulated, 1.01-8.40-fold) were involved in defense responses in endophytic fungi symbiotic tissue cultured seedlings. The protein-protein interaction (PPI) network demonstrated that genes encoding CHS (VIT_10s0042g00920, VIT_14s0068g00920, and VIT_16s0100g00910) and the VIT_11s0065g00350 gene encoding CYP73A mediated the defense responses, and might induce more defense-associated metabolites. These results illustrated the activation of stress-associated secondary metabolism in the host grapevine during the establishment of fungi-plant endophytism. This work provides avenues for reshaping the qualities and characteristics of wine grapes utilizing specific endophytes and better understanding plant-microbe interactions.
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BACKGROUND: Renin-dependent hypertension with tubulointerstitial injury remains a problem with high prevalence in the clinic. However, whether and how renin participates in tubulointerstitial injury remains incompletely understood. New evidence suggests that renin cleaves C3 into C3a and C3b. In the present study, we aimed to explore the role of renin-mediated C3a/C3a receptor (C3aR) signaling in renin-dependent hypertension-induced kidney injury and illustrate the detailed mechanisms. METHODS: C3a concentration changes in serum from healthy volunteers incubated with recombinant renin were detected by ELISA. C3aR expression in human tubular epithelial cells was evaluated in renal biopsy sections from malignant arteriolonephrosclerosis and benign arteriolonephrosclerosis patients. C3aR changes in human kidney 2 (HK2) cells were detected after the cells were treated with human serum, renin and aliskiren. The C3a analogue and C3aR antagonist SB290157 were used to stimulate HK2 cells to explore the downstream signaling of C3a/C3aR activation. For in vivo studies, two-kidney, one-clipped (2K1C) hypertensive rat model was established to simulate renin-dependent hypertension conditions. C3a and C3aR expression was detected in the clipped kidneys. SB290157 was injected intraperitoneally to block C3a/C3aR signaling in 2K1C rats. RESULTS: The results showed that renin cleaved C3 into C3a and activated C3a/C3aR signaling in tubular epithelial cells (TECs) from both humans and rats. In vitro results demonstrated that C3a/C3aR activation impaired peroxisome proliferator-activated receptor alpha (PPARα)/carnitine palmitoyltransterase-1alpha (CPT-1α)-mediated mitochondrial fatty acid oxidation (Mito FAO) in HK2 cells and induced HK2 cell transition to a profibrotic phenotype, which was inhibited by treatment with the C3aR antagonist SB290157. In vivo results showed that renin mRNA levels, C3a concentrations, C3aR levels and tubulointerstitial fibrosis increased concurrently in the clipped kidney cortex of 2K1C rats. Treatment with the C3aR antagonist SB290157 significantly mitigated the effect of renin induction of C3aR expression and alleviated renin-dependent hypertension-induced tubulointerstitial fibrosis by improving PPARα/CPT-1α-mediated Mito FAO in TECs, as well as inhibiting tubular profibrotic phenotype transition. CONCLUSIONS: Our results prove that renin activates C3a/C3aR signaling to promote renal tubulointerstitial fibrosis by impairing PPARα/CPT-1α-mediated tubular Mito FAO. SB290157 confers a potential therapeutic approach for renin-dependent hypertension-induced kidney injury.
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Hipertensão Renal , PPAR alfa , Humanos , Ratos , Animais , Renina/genética , Carnitina , Ácidos Graxos , Fenótipo , FibroseRESUMO
Introduction: The aim of this study was to develop and validate a risk score (RS) for end-stage kidney disease (ESKD) in patients with focal segmental glomerulosclerosis (FSGS). Methods: Patient with biopsy-proven FSGS was enrolled. All the patients were allocated 1:1 to the two groups according to their baseline gender, age, and baseline creatinine level by using a stratified randomization method. ESKD was the primary endpoint. Results: We recruited 359 FSGS patients, and 177 subjects were assigned to group 1 and 182 to group 2. The clinicopathological variables were similar between two groups. There were 23 (13%) subjects reached to ESKD in group 1 and 22 (12.1%) in group 2. By multivariate Cox regression analyses, we established RS 1 and RS 2 in groups 1 and 2, respectively. RS 1 consists of five parameters including lower eGFR, higher urine protein, MAP, IgG level, and tubulointerstitial lesion (TIL) score; RS 2 also consists of five predictors including lower C3, higher MAP, IgG level, hemoglobin, and TIL score. RS 1 and RS 2 were cross-validated between these two groups, showing RS 1 had better performance in predicting 5-year ESKD in group 1 (c statics, 0.86 [0.74-0.98] vs. 0.82 [0.69-0.95]) and group 2 (c statics, 0.91 [0.83-0.99] vs. 0.89 [0.79-0.99]) compared to RS 2. We then stratified the risk factors into four groups, and Kaplan-Meier survival curve revealed that patients progressed to ESKD increased as risk levels increased. Conclusions: A predictive model incorporated clinicopathological feature was developed and validated for the prediction of ESKD in FSGS patients.
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BACKGROUND: Membranous nephropathy (MN) is a major pattern of nephrotic syndrome (NS) in adults. Some MN have secondary causes and some may be accompanied with other glomerular diseases. MN patients coexisting with amyloidosis are very rare, and mostly was polytypic MN. Herein, we describe the first report which identifying monotype PLA2R-MN (κ light chain) concurrent with leukocyte chemotactic factor 2 amyloidosis (ALECT2). This rare case highlights the importance of renal pathology for diagnosis. CASE PRESENTATION: We describe a case of a 60-year-old male patient with persistent proteinuria and low serum albumin for nine months. No monoclonal component was revealed by serum and urine immunofixation electrophoresis but serum PLA2R antibody was positive. The patient was empirically treated with Leflunomide and Losartan, but edema was not improved. The diagnosis of renal pathology is PLA2R-related monotypic (IgG-κ positive) MN concurrent with ALECT2. Methylprednisolone, cyclosporine A and anticoagulant (rivaroxaban) were prescribed resulting in a complete remission of NS. CONCLUSIONS: MN patients concurrent with ALECT2 presented massive proteinuria or NS. When nephrotic range proteinuria is present in ALECT2, it is important to consider that it may be due to a concomitant underlying nephropathy especially MN and treated according to MN will get good therapeutic effect.
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Amiloidose , Glomerulonefrite Membranosa , Síndrome Nefrótica , Adulto , Masculino , Humanos , Pessoa de Meia-Idade , Glomerulonefrite Membranosa/complicações , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/tratamento farmacológico , Síndrome Nefrótica/complicações , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/tratamento farmacológico , Proteinúria , Amiloidose/complicações , Amiloidose/diagnóstico , Fatores Quimiotáticos , Leucócitos , Imunoglobulina GRESUMO
Mesenchymal stem cells (MSCs) transplantation is a promising approach for pulmonary fibrosis (PF), however it is impeded by several persistent challenges, including the lack of long-term tracking, low retention, and poor survival of MSCs, as well as the low labeling efficiency of nanoprobes. Herein, a cobalt protoporphyrin IX (CoPP) aggregation-induced strategy is applied to develop a multifunctional nano-self-assembly (ASCP) by combining gold nanoparticle (AuNPs), superparamagnetic iron oxide nanoparticles (SPIONs), and CoPP through a facile solvent evaporation-driven approach. Since no additional carrier materials are employed during the synthesis, high loading efficiency of active ingredients and excellent biocompatibility are achieved. Additionally, facile modification of the ASCPs with bicyclo[6.1.0]nonyne (BCN) groups (named as ASCP-BCN) enables them to effectively label MSCs through bioorthogonal chemistry. The obtained ASCP-BCN could not only help to track MSCs with AuNP-based computed tomography (CT) imaging, but also achieve an SPIONs-assisted magnetic field based improvement in the MSCs retention in lungs as well as promoted the survival of MSCs via the sustained release of CoPP. The in vivo results demonstrated that the labeled MSCs improved the lung functions and alleviated the fibrosis symptoms in a bleomycin-induced PF mouse model. Collectively, a novel ASCP-BCN multifunctional nanoagent was developed to bioorthogonally-label MSCs with a high efficiency, presenting a promising potential in the high-efficient MSC therapy for PF.
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Focal segmental glomerulosclerosis (FSGS) is a histological lesion with a variety of potential causes, including rare variants of podocyte-related genes. Recently, it has been found that variants in the TBC1D8B gene on the X chromosome can lead to early-onset focal segmental glomerulosclerosis and steroid-resistant nephrotic syndrome by affecting endocytosis and recycling of nephrin. Here, we report a 19-year-old Chinese patient with nephrotic syndrome and normal kidney function. He had a complete remission of nephrotic syndrome after full-dose prednisone and cyclosporine treatment. Unfortunately, a relapse of nephrotic syndrome occurred during prednisone tapering. Focal segmental glomerulosclerosis was proven by a kidney biopsy, and a hemizygous pathogenic variant located in the TBC (Tre-2-Bub2-Cdc16) domain of TBC1D8B was detected by whole-exome sequencing. By comparing our case with reports of other patients with TBC1D8B variants, we suggest possible genotype-phenotype correlations. To our knowledge, this is the first report identifying a pathogenetic variant in the TBC domain of TBC1D8B in an adult-onset focal segmental glomerulosclerosis patient with steroid-dependent NS. With this report, we broaden the clinical and genetic spectrum of X-linked genetic FSGS.
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Glomerulosclerose Segmentar e Focal , Síndrome Nefrótica , Podócitos , Masculino , Humanos , Síndrome Nefrótica/tratamento farmacológico , Síndrome Nefrótica/genética , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Glomerulosclerose Segmentar e Focal/genética , Prednisona/uso terapêutico , Ciclosporina/uso terapêutico , Podócitos/patologiaRESUMO
BACKGROUND: This study aimed to examine the clinicopathological profiles and prognosis of membranous nephropathy in different subtypes classified by serum PLA2R antibody (SAb) and glomerular PLA2R antigen staining (GAg). METHODS: A total of 372 biopsy-proven membranous nephropathy (MN) cases, unrelated to lupus, with urine protein > 2 g/24 h and eGFR > 25 mL/min/1.73 m2 were included and categorized into four groups according to the presence or absence of PLA2R antibody and glomerular PLA2R antigen staining. Clinical profiles were compared among four subtypes. Treatment response and renal outcomes were compared among four groups with primary MN. Cox and logistic regression models were used to examine the association between time-to-renal progression and early remission within 6 months in the four subgroups with primary MN. RESULTS: MN patients who were SAb-/GAg+ presented with a more severe disease onset, whereas those who were SAb-/GAg- had a mild clinical manifestation with a higher prevalence of MN-associated secondary causes. During a median follow-up of 79.2 months (IQR: 48.70-97.40), SAb+/GAg- was identified as an independent risk factor for renal progression [HR: 9.17, 95% CI: 2.26-37.16, p < 0.01] and early remission [OR: 0.06, 95% CI: 0.01-0.56, p = 0.01] in primary MN. Additionally, SAb-/GAg- with primary MN showed an independent association with spontaneous remission after adjusting for age, sex, baseline proteinuria, and eGFR (Before adjustment: OR: 8.33, 95% CI: 1.89-36.76, p = 0.0; after adjustment: OR: 12.25, 95% CI: 2.48-60.53, p < 0.01). CONCLUSION: Our findings indicated that SAb+/GAg-MN patients exhibited a more severe disease onset and had a poorer prognosis, necessitating an aggressive treatment approach. On the other hand, in the SAb-/GAg- group, the elimination of secondary causes should be considered, and a watchful waiting approach may be appropriate.
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BACKGROUND: Focal and segmental glomerulosclerosis (FSGS) is a histological pathology that characterizes a wide spectrum of diseases. Many genes associated with FSGS have been studied previously, but there are still some FSGS families reported in the literature without the identification of known gene mutations. The aim of this study was to investigate the new genetic cause of adult-onset FSGS. METHODS: This study included 40 FSGS families, 77 sporadic FSGS cases, 157 non-FSGS chronic kidney disease (CKD) families and 195 healthy controls for analyses. Whole-exome sequencing (WES) and Sanger sequencing were performed on probands and family members of all recruited families and sporadic FSGS cases. RESULTS: Using WES, we have identified a novel heterozygous missense variant (c.T1655C:p.V552A) in exportin 5 gene (XPO5) in two families (FS-133 and CKD-05) affected with FSGS and CKD. Sanger sequencing has confirmed the co-segregation of this identified variant in an autosomal dominant pattern within two families, while this variant was absent in healthy controls. Furthermore, the identified mutation was absent in 195 ethnically matched healthy controls by Sanger sequencing. Subsequently, in silico analysis demonstrated that the identified variant was highly conservative in evolution and likely to be pathogenic. CONCLUSIONS: Our study reports an adult-onset autosomal dominant inheritance of the XPO5 variant in familial FSGS for the first time. Our study expanded the understanding of the genotypic, phenotypic and ethnical spectrum of mutation in this gene.
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Glomerulosclerose Segmentar e Focal , Insuficiência Renal Crônica , Adulto , Humanos , Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/patologia , Mutação , Sequenciamento do Exoma , Heterozigoto , Linhagem , Carioferinas/genéticaRESUMO
Endophytes and their elicitors can all be utilized in regulating crop biochemical qualities. However, living endophytes and their derived elicitors are always applied separately; little is known about the similarities and differences of their effects. To increase the efficiency of this system when applied in practice, the present work profiled simultaneously the metabolomes in grape cells exposed to endophytic fungi (EF) and their corresponding fungal extracts (CFE). As expected, grape cells exposed separately to different fungi, or to different fungi derived extracts, each exhibited different modifications of metabolite patterns. The metabolic profiles of certain EF- and CFE-exposed grape cells were also differently influenced to certain degrees, owing to the presence of differentially responding metabolites (DRMs). However, the detected majority proportions of coordinately responding metabolites (CRMs) in both the EF- and the CFE-exposed grape cells, as well as the significantly influenced metabolites (SIMs) which are specific to certain fungal strains, clearly indicate coordinative changes in metabolites in grape cells exposed to EF and CFEs. The coordinative changes in metabolites in EF- and CFE-treated grape cells appeared to be fungal strain-dependent. Notably, several of those fungal strain-specific CRMs and DRMs are metabolites and belong to amino acids, lipids, organic acids, phenolic acids, flavonoids, and others, which are major contributors to the biochemistry and sensory qualities of grapes and wines. This research clarifies the detailed responses of metabolites in grape cells exposed to EF and CFEs. It also demonstrates how endophytes can be selectively used in the form of extracts to produce functions as CRMs of the living fungus with increased eco-safety, or separately applied to the living microbes or elicitors to emphasize those effects related to their specifically initiated SIMs and DRMs.
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Vitis , Vinho , Endófitos/metabolismo , Fungos/metabolismo , Metaboloma , Vitis/metabolismoRESUMO
BACKGROUND: Fabry disease (FD, OMIM #301500) is an X-linked lysosomal disorder caused by the deficiency of α-galactosidase A (α-GalA), encoded by the GLA gene. Among more than 1100 reported GLA mutations, few were deep intronic mutations which have been linked to classic and cardiac variants of FD. METHODS AND RESULTS: We report a novel hemizygous deep intronic GLA mutation (IVS4+1326C>T) in a 33-year-old Chinese man with a mild α-GalA deficiency phenotype involving isolated proteinuria and predominant globotriaosylceramide deposits in podocytes. IVS4+1326C>T, which appears to be the first deep intronic GLA mutation associated with renal variant of FD, was identified by Sanger sequencing the entire GLA genomic DNA sequence of the patient's peripheral mononuclear blood lymphocytes (PBMCs). Further sequencing of cDNA from PBMCs of the patient revealed a minor full-length GLA transcript accounting for about 25% of total GLA transcript, along with two major aberrantly spliced GLA transcripts encoding mutant forms of α-GalA with little enzyme activity characterized by in vitro α-GalA overexpression system in the HEK293T cells. Thus, the combined clinical phenotype, genetic analysis and functional studies verified the pathogenicity of IVS4+1326C>T. CONCLUSIONS: The identification of IVS4+1326C>T establishes a link between deep intronic GLA mutation and the renal variant of FD, which extends the mutation spectrum in GLA gene and justifies further study of how IVS4+1326C>T and potentially other deep intronic GLA mutations contribute to Fabry podocytopathy through aberrant splicing. Future studies should also assess the true incidence of IVS4+1326C>T in patients with different variants of FD, which may improve early genetic diagnosis to allow timely treatment that can prevent disease progression and improve survival.
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Doença de Fabry , Doença de Fabry/diagnóstico , Células HEK293 , Humanos , Rim , Mutação/genética , alfa-Galactosidase/genéticaRESUMO
To examine the retinal and choroidal changes in patients with Fabry disease (FD) using optical coherence tomography angiography (OCTA). FD patients and age- and sex-matched healthy subjects were enrolled. A detailed ophthalmological examination was performed for all participants. The retinal thickness, ganglion cell layer with inner plexiform layer (GCIPL) thickness, choroidal thickness (CT), vessel length density (VLD), vessel perfusion density (VPD), and foveal avascular zone (FAZ) were analyzed in a detailed way with OCTA. Moreover, all FD patients underwent several laboratory tests to evaluate systemic conditions. A total of 54 subjects comprising 26 FD patients and 28 normal controls were enrolled. The retinal thickness, GCIPL thickness, and FAZ area showed no significant differences between the two groups (all P > 0.05). Only the superior CT in FD patients was significantly thinner than that in the normal subjects (P = 0.040). The macular VLD and VPD in the FD group were significantly reduced compared with the healthy controls (P = 0.026, P = 0.008). The macular VLD in FD patients had no significant correlations with different laboratory results (all P > 0.05), while the macular VPD were negatively correlated with creatinine (r = - 0.432, P = 0.028) and cystatin C (r = - 0.422, P = 0.032). FD patients may have retinal vascular dropout and choroidal vascular alterations. Analysis of vessel density using OCTA might be useful in the clinical assessment in FD patients.
Assuntos
Doença de Fabry , Tomografia de Coerência Óptica , Corioide/diagnóstico por imagem , Doença de Fabry/diagnóstico por imagem , Angiofluoresceinografia , Humanos , Vasos Retinianos/diagnóstico por imagemRESUMO
The metabolic patterns of grape cells can be specifically shaped by different strains of dual-cultured fungal endophytes. In this work, a solid co-culture system was furtherly proposed to illustrate the different impacts of endophytic fungi on the biochemical status of grape cells of different varieties. By measuring the metabolic impacts of contact fungal endophytes on grape cells of the varieties 'Rose honey' (RH) and 'Cabernet sauvignon' (CS), we observed that most of the fungal strains used had promoting effects on grape cellular biochemistry parameters. Compared with the control, inoculation with most of the fungal strains increased the superoxide dismutase (SOD) and phenylalanine ammonia-lyase (PAL) activities as well as the total flavonoid (TF) and total phenolics (TPh) contents in both types of grape cells. Among the tested strains, RH34, RH49 and MDR36 had relatively stronger biochemical impacts on grape cells. More interestingly, in addition to the varietal specificity, a certain degree of fungal genus specificity was also observed during the metabolic interactions between fungal endophytes and grape cells, as fungal endophytes from the same genus tended to be clustered into the same group based on the affected biochemical traits. This work revealed the differential biochemical status effects of fungal endophytes on different varietal grape cells and raised the possibility of reshaping grape qualities by applying endophytes.
RESUMO
Renal amyloidosis typically manifests albuminuria, nephrotic-range proteinuria, and ultimately progresses to end-stage renal failure if diagnosed late. Different types of renal amyloidosis have completely different treatments and outcomes. Therefore, amyloidosis typing is essential for disease prognosis, genetic counseling and treatment. Thirty-six distinct proteins currently known to cause amyloidosis that have been described as amyloidogenic precursors, immunohistochemistry (IHC) or immunofluorescence (IF), can be challenging for amyloidosis typing especially in rare or hereditary amyloidosis in clinical practice. We made a pilot study that optimized the proteomics pre-processing procedures for trace renal amyloidosis formalin-fixed paraffin-embedded (FFPE) tissue samples, combined with statistical and bioinformatics analysis to screen out the amyloidosis-related proteins to accurately type or subtype renal amyloidosis in order to achieve individual treatment. A sensitive, specific and reliable FFPE-based proteomics analysis for trace sample manipulation was developed for amyloidosis typing. Our results not only underlined the great promise of traditional proteomics and bioinformatics analysis using FFPE tissues for amyloidosis typing, but also proved that retrospective diagnosis and analysis of previous cases laid a solid foundation for personalized treatment.
Assuntos
Amiloidose/metabolismo , Formaldeído/química , Rim/patologia , Inclusão em Parafina , Proteômica , Fixação de Tecidos , Amiloidose/genética , Amiloidose/patologia , Sequência de Bases , Estudos de Casos e Controles , Humanos , Espectrometria de Massas , Muramidase/metabolismo , Projetos PilotoRESUMO
We aimed to validate three IgAN risk models proposed by an international collaborative study and another CKD risk model generated by an extended CKD cohort with our multicenter Chinese IgAN cohort. Biopsy-proven IgAN patients with an eGFR ≥15 ml/min/1.73 m2 at baseline and a minimum follow-up of 6 months were enrolled. The primary outcomes were a composite outcome (50% decline in eGFR or ESRD) and ESRD. The performance of those models was assessed using discrimination, calibration, and reclassification. A total of 2,300 eligible cases were enrolled. Of them, 288 (12.5%) patients reached composite outcome and 214 (9.3%) patients reached ESRD during a median follow-up period of 30 months. Using the composite outcome for analysis, the Clinical, Limited, Full, and CKD models had relatively good performance with similar C statistics (0.81, 0.81, 0.82, and 0.82, respectively). While using ESRD as the end point, the four prediction models had better performance (all C statistics > 0.9). Furthermore, subgroup analysis showed that the models containing clinical and pathological variables (Full model and Limited model) had better discriminatory abilities than the models including only clinical indicators (Clinical model and CKD model) in low-risk patients characterized by higher baseline eGFR (≥60 ml/min/1.73 m2). In conclusion, we validated recently reported IgAN and CKD risk models in our Chinese IgAN cohort. Compared to pure clinical models, adding pathological variables will increase performance in predicting ESRD in low-risk IgAN patients with baseline eGFR ≥60 ml/min/1.73 m2.