Small extracellular vesicles-shuttled miR-23a-3p from mesenchymal stem cells alleviate renal fibrosis and inflammation by inhibiting KLF3/STAT3 axis in diabetic kidney disease.

Human umbilical cord mesenchymal stem cells-derived small extracellular vesicles (MSC-sEV) provide a pragmatic solution as a cell-free therapy for patients with diabetic kidney disease (DKD). However, the underlying protective mechanisms of MSC-sEV remain largely unknown in DKD. Invivo and in vitro analyses demonstrated that MSC-sEV attenuated renal fibrosis and inflammation of DKD. The underlying mechanism of the MSC-sEV-induced therapeutic effect was explored by high-throughput sequencing, which identified the unique enrichment of a set of miRNAs in MSC-sEV compared with human skin fibroblasts-sEV (HSF-sEV). Vitro experiments demonstrated that the protective potential was primarily attributed to miR-23a-3p, one of the most abundant miRNAs in MSC-sEV. Further, overexpression or knockdown analyses revealed that miR-23a-3p, and its target Krüppel-like factor 3 (KLF3) suppressed the STAT3 signaling pathway in high glucose (HG) induced HK-2 cells were essential for the renal-protective property of MSC-sEV. Moreover, we found that miR-23a-3p was packaged into MSC-sEV by RNA Binding Motif Protein X-Linked (RBMX) and transmitted to HG-induced HK-2 cells. Finally, inhibiting miR-23a-3p could mitigate the protective effects of MSC-sEV in db/db mice. These findings suggest that a systemic administration of sEV derived from MSC, have the capacity to incorporate into kidney where they can exert renal-protective potential against HG-induced injury through delivery of miR-23a-3p.

Mesenchymal stem cell-derived exosomes ameliorate diabetic kidney disease through NOD2 signaling pathway.

BACKGROUND AND AIMS: Diabetic kidney disease (DKD) is one of the most common complications of diabetes. It is reported that mesenchymal stem cells (MSCs) derived exosomes (MSCs-Exo) may have great clinical application potential for the treatment of DKD, but the underlying mechanism has not been illustrated. To clarify the effect of MSC-Exo on NOD2 signaling pathway in podocytes under high glucose (HG) and DKD, we conduct this study. METHODS: We co-cultured podocytes and MSCs-Exo under 30 mM HG and injected MSCs-Exo into DKD mice, then we detected the NOD2 signaling pathway by western blot, qRT-PCT, immunofluorescence, transmission electron microscopy and immunohistochemistry both in vitro and in vivo. RESULTS: In vitro, HG lead to the apoptosis, increased the ROS level and activated the NOD2 signaling pathway in podocytes, while MSCs-Exo protected podocytes from injury reduced the expression of inflammatory factors including TNF-α, IL-6, IL-1ß, and IL-18 and alleviated the inflammatory response, inhibited the activation of NOD2 signaling pathway and the expression of it's downstream protein p-P65, p-RIP2, prevented apoptosis, increased cell viability in podocytes caused by HG. In vivo, MSCs-Exo alleviated renal injury in DKD mice, protected renal function, decreased urinary albumin excretion and inhibited the activation of NOD2 signaling pathway as well as the inflammation in renal tissue. CONCLUSION: MSCs-Exo protected the podocytes and DKD mice from inflammation by mediating NOD2 pathway, MSCs-Exo may provide a new target for the treatment of DKD.

Deep-learning segmentation to select liver parenchyma for categorizing hepatic steatosis on multinational chest CT.

Unenhanced CT scans exhibit high specificity in detecting moderate-to-severe hepatic steatosis. Even though many CTs are scanned from health screening and various diagnostic contexts, their potential for hepatic steatosis detection has largely remained unexplored. The accuracy of previous methodologies has been limited by the inclusion of non-parenchymal liver regions. To overcome this limitation, we present a novel deep-learning (DL) based method tailored for the automatic selection of parenchymal portions in CT images. This innovative method automatically delineates circular regions for effectively detecting hepatic steatosis. We use 1,014 multinational CT images to develop a DL model for segmenting liver and selecting the parenchymal regions. The results demonstrate outstanding performance in both tasks. By excluding non-parenchymal portions, our DL-based method surpasses previous limitations, achieving radiologist-level accuracy in liver attenuation measurements and hepatic steatosis detection. To ensure the reproducibility, we have openly shared 1014 annotated CT images and the DL system codes. Our novel research contributes to the refinement the automated detection methodologies of hepatic steatosis on CT images, enhancing the accuracy and efficiency of healthcare screening processes.

Nomogram based on preoperative clinical and MRI features to estimate the microvascular invasion status and the prognosis of solitary intrahepatic mass-forming cholangiocarcinoma.

PURPOSE: To develop a nomogram based on preoperative clinical and magnetic resonance imaging (MRI) features for the microvascular invasion (MVI) status in solitary intrahepatic mass-forming cholangiocarcinoma (sIMCC) and to evaluate whether it could predict recurrence-free survival (RFS). METHODS: We included 115 cases who experienced MRI examinations for sIMCC with R0 resection. The preoperative clinical and MRI features were extracted. Independent predictors related to MVI+ were evaluated by stepwise multivariate logistic regression, and a nomogram was constructed. A receiver operating characteristic (ROC) curve was used to assess the predictive ability. All patients were classified into high- and low-risk groups of MVI. Then, the correlations of the nomogram with RFS in patents with sIMCC were analyzed by Kaplan-Meier method. RESULTS: The occurrence rate of MVI+ was 38.3% (44/115). The preoperative independent predictors of MVI+ were carbohydrate antigen 19-9 > 37 U/ml, tumor size > 5 cm, and an ill-defined tumor boundary. Integrating these predictors, the nomogram exerted a favorable diagnostic performance with areas under the ROC curve of 0.767 (95% confidence interval [CI] 0.654-0.881) in the development cohort, and 0.760 (95% CI 0.591-0.929) in the validation cohort. In the RFS analysis, significant differences were observed between the high- and low-risk MVI groups (6-month RFS rates: 64.5% vs. 78.8% and 46.7% vs. 82.4% in the development and validation cohorts, respectively) (P < 0.05). CONCLUSIONS: A nomogram based on clinical and MRI features is a potential biomarker of MVI and may be a potent method to classify the risk of recurrence in patients with sIMCC.

MRI-based Multiregional Radiomics for Pretreatment Prediction of Distant Metastasis After Neoadjuvant Chemoradiotherapy in Patients with Locally Advanced Rectal Cancer.

RATIONALE AND OBJECTIVES: To develop and validate a nomogram based on intratumoral and peritumoral radiomics signatures for pretreatment prediction of distant metastasis-free survival (DMFS) in patients after neoadjuvant chemoradiotherapy (NCRT) with locally advanced rectal cancer (LARC). MATERIALS AND METHODS: This retrospective study included 230 patients (161 training cohort; 69 validation cohort) with LARC who underwent NCRT and surgery. Radiomics features were extracted on T2-weighted images from gross tumor volume (GTV) and volumes of 4-mm, 6-mm, and 8-mm peritumoral regions (PTV4, PTV6, and PTV8). The least absolute shrinkage and selection operator (LASSO)-Cox analysis were used for features selection and models construction. The performance of each model in predicting DMFS was evaluated by the Concordance index (C-index) and time-independent receiver operating characteristic curve (ROC). RESULTS: The PTV4 radiomics model demonstrated superior performance compared to the PTV6 and PTV8 radiomics models, with C-indexes of 0.750 and 0.703 in the training and validation cohorts, respectively. The nomogram was constructed by integrating the GTV radiomics signature, PTV4 radiomics signature, and relevant clinical characteristics, including CA19-9 level, clinical T stage, and clinical N stage. The nomogram achieved C-indexes of 0.831 and 0.748, with corresponding AUCs of 0.872 and 0.808 for 5-year DMFS in the training and validation cohorts, respectively. Kaplan-Meier analysis revealed that a cut-off value of 1.653 effectively stratified patients into high- and low-risk groups for DM (P < 0.001). CONCLUSION: The intra-peritumoral radiomics nomogram is a favorable tool for clinicians to develop personalized systemic treatment and intensive follow-up strategies to improve patient prognosis.

Risk stratification for overall survival and recurrence-free survival after R0 resection for solitary intrahepatic mass-forming cholangiocarcinoma based on preoperative MRI and clinical features.

PURPOSE: This study aimed to establish two nomograms for predicting overall survival (OS) and recurrence-free survival (RFS) in patients with solitary intrahepatic mass-forming cholangiocarcinoma (IMCC) based on preoperative magnetic resonance imaging (MRI) features. METHODS: This retrospective study included 120 consecutive patients who were diagnosed with solitary IMCC. Preoperative MRI and clinical features were collected. Based on the univariate and multivariate Cox regression analyses, two nomograms were constructed to predict OS and RFS, respectively. The effective performance of the nomograms was evaluated using concordance index (C-index). The prognostic stratification systems for OS and RFS were developed and used to classify patients into high- and low-risk groups. RESULTS: Suspicious lymph nodes, arterial phase (AP) enhancement patterns, and bile duct dilatation were independent predictors of OS, while suspicious lymph nodes, AP enhancement patterns, and necrosis were independent predictors of RFS. The nomograms achieved the C-index values of 0.705/0.710 for OS and 0.721/0.759 for RFS in the development/validation cohorts, which were significantly higher than those of the T and TNM stages (P < 0.05). Patients were stratified into high- and low-risk groups, the 1-year OS and RFS rates of high-risk patients were poorer than those of patients with low-risk in the development cohort (OS: 93.5% vs 76.3%, P < 0.001; RFS: 74.5% vs 22.4%, P < 0.001). Similar results were observed in the validation cohort. CONCLUSIONS: Two nomograms were constructed based on preoperative MRI features in patients with solitary IMCC for predicting the OS and RFS and facilitate further prognostic stratification.

CUI-Net: a correcting uneven illumination net for low-light image enhancement.

Uneven lighting conditions often occur during real-life photography, such as images taken at night that may have both low-light dark areas and high-light overexposed areas. Traditional algorithms for enhancing low-light areas also increase the brightness of overexposed areas, affecting the overall visual effect of the image. Therefore, it is important to achieve differentiated enhancement of low-light and high-light areas. In this paper, we propose a network called correcting uneven illumination network (CUI-Net) with sparse attention transformer and convolutional neural network (CNN) to better extract low-light features by constraining high-light features. Specifically, CUI-Net consists of two main modules: a low-light enhancement module and an auxiliary module. The enhancement module is a hybrid network that combines the advantages of CNN and Transformer network, which can alleviate uneven lighting problems and enhance local details better. The auxiliary module is used to converge the enhancement results of multiple enhancement modules during the training phase, so that only one enhancement module is needed during the testing phase to speed up inference. Furthermore, zero-shot learning is used in this paper to adapt to complex uneven lighting environments without requiring paired or unpaired training data. Finally, to validate the effectiveness of the algorithm, we tested it on multiple datasets of different types, and the algorithm showed stable performance, demonstrating its good robustness. Additionally, by applying this algorithm to practical visual tasks such as object detection, face detection, and semantic segmentation, and comparing it with other state-of-the-art low-light image enhancement algorithms, we have demonstrated its practicality and advantages.

A PET/CT nomogram incorporating SUVmax and CT radiomics for preoperative nodal staging in non-small cell lung cancer.

OBJECTIVES: To develop and validate a PET/CT nomogram for preoperative estimation of lymph node (LN) staging in patients with non-small cell lung cancer (NSCLC). METHODS: A total of 263 pathologically confirmed LNs from 124 patients with NCSLC were retrospectively analyzed. Positron-emission tomography/computed tomography (PET/CT) examination was performed before treatment according to the clinical schedule. In the training cohort (N = 185), malignancy-related features, such as SUVmax, short-axis diameter (SAD), and CT radiomics features, were extracted from the regions of LN based on the PET/CT scan. The Minimum-Redundancy Maximum-Relevance (mRMR) algorithm and the Least Absolute Shrinkage and Selection Operator (LASSO) regression model were used for feature selection and radiomics score building. The radiomics score (Rad-Score) and SUVmax were incorporated in a PET/CT nomogram using the multivariable logistic regression analysis. The performance of the proposed model was evaluated with discrimination, calibration, and clinical application in an independent testing cohort (N = 78). RESULTS: The radiomics scores consisting of 14 selected features were significantly associated with LN status for both training cohort with AUC of 0.849 (95% confidence interval (CI), 0.796-0.903) and testing cohort with AUC of 0.828 (95% CI, 0.782-0.919). The PET/CT nomogram incorporating radiomics score and SUVmax showed moderate improvement of the efficiency with AUC of 0.881 (95% CI, 0.834-0.928) in the training cohort and AUC of 0.872 (95% CI, 0.797-0.946) in the testing cohort. The decision curve analysis indicated that the PET/CT nomogram was clinically useful. CONCLUSION: The PET/CT nomogram, which incorporates Rad-Score and SUVmax, can improve the diagnostic performance of LN metastasis. KEY POINTS: • The PET/CT nomogram (Int-Score) based on lymph node (LN) PET/CT images can reliably predict LN status in NSCLC. • Int-Score is a relatively objective diagnostic method, which can play an auxiliary role in the process of clinicians making treatment decisions.

A Novel Multimodal Radiomics Model for Preoperative Prediction of Lymphovascular Invasion in Rectal Cancer.

Objective: To explore a new predictive model of lymphatic vascular infiltration (LVI) in rectal cancer based on magnetic resonance (MR) and computed tomography (CT). Methods: A retrospective study was conducted on 94 patients with histologically confirmed rectal cancer, they were randomly divided into training cohort (n = 65) and validation cohort (n = 29). All patients underwent MR and CT examination within 2 weeks before treatment. On each slice of the tumor, we delineated the volume of interest on T2-weighted imaging, diffusion weighted imaging, and enhanced CT images, respectively. A total of 1,188 radiological features were extracted from each patient. Then, we used the student t-test or Mann-Whitney U-test, Spearman's rank correlation and least absolute shrinkage and selection operator (LASSO) algorithm to select the strongest features to establish a single and multimodal logic model for predicting LVI. Receiver operating characteristic (ROC) curves and calibration curves were plotted to determine how well they explored LVI prediction performance in the training and validation cohorts. Results: An optimal multi-mode radiology nomogram for LVI estimation was established, which had significant predictive power in training (AUC, 0.884; 95% CI, 0.803-0.964) and validation (AUC, 0.876; 95% CI, 0.721-1.000). Calibration curve and decision curve analysis showed that the multimodal radiomics model provides greater clinical benefits. Conclusion: Multimodal (MR/CT) radiomics models can serve as an effective visual prognostic tool for predicting LVI in rectal cancer. It demonstrated great potential of preoperative prediction to improve treatment decisions.

Multiregional-Based Magnetic Resonance Imaging Radiomics Combined With Clinical Data Improves Efficacy in Predicting Lymph Node Metastasis of Rectal Cancer.

OBJECTIVE: To develop and validate a multiregional-based magnetic resonance imaging (MRI) radiomics model and combine it with clinical data for individual preoperative prediction of lymph node (LN) metastasis in rectal cancer patients. METHODS: 186 rectal adenocarcinoma patients from our retrospective study cohort were randomly selected as the training (n = 123) and testing cohorts (n = 63). Spearman's rank correlation coefficient and the least absolute shrinkage and selection operator were used for feature selection and dimensionality reduction. Five support vector machine (SVM) classification models were built using selected clinical and semantic variables, single-regional radiomics features, multiregional radiomics features, and combinations, for predicting LN metastasis in rectal cancer. The performance of the five SVM models was evaluated via the area under the receiver operator characteristic curve (AUC), accuracy, sensitivity, and specificity in the testing cohort. Differences in the AUCs among the five models were compared using DeLong's test. RESULTS: The clinical, single-regional radiomics and multiregional radiomics models showed moderate predictive performance and diagnostic accuracy in predicting LN metastasis with an AUC of 0.725, 0.702, and 0.736, respectively. A model with improved performance was created by combining clinical data with single-regional radiomics features (AUC = 0.827, (95% CI, 0.711-0.911), P = 0.016). Incorporating clinical data with multiregional radiomics features also improved the performance (AUC = 0.832 (95% CI, 0.717-0.915), P = 0.015). CONCLUSION: Multiregional-based MRI radiomics combined with clinical data can improve efficacy in predicting LN metastasis and could be a useful tool to guide surgical decision-making in patients with rectal cancer.

Comprehensive analysis of aberrantly expressed profiles of mRNA and its relationship with serum galactose-deficient IgA1 level in IgA nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the leading cause of end-stage kidney disease. Previous mRNA microarray profiling studies of IgAN revealed inconsistent data. We sought to identify the aberrantly expressed genes and biological pathways by integrating IgAN gene expression datasets in blood cells and performing systematically experimental validation. We also explored the relationship between target genes and galactose-deficient IgA1 (Gd-IgA1) in IgAN. METHODS: We retrieved Gene Expression Omnibus (GEO) datasets of IgAN. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used for functional analysis. Deep sequencing on RNA isolated from B cells was used for microarray validation. The relationship between target mRNA expressions and Gd-IgA1 levels in serum were also studied. RESULTS: Three studies with microarray expression profiling datasets met our inclusion criteria. We identified 655 dyregulated genes, including 319 up-regulated and 336 down-regulated genes in three GEO datasets with a total of 35 patients of IgAN and 19 healthy controls. Based on biological process in GO term, these dyregulated genes are mainly related to pentose-phosphate shunt, non-oxidative branch, post-embryonic camera-type eye development and leukocyte activation. KEGG pathway analysis of microarray data revealed that these aberrantly expressed genes were enriched in human T-cell leukemia virus 1 infection, proteoglycans in cancer, intestinal immune network for IgA production and autophagy. We further performed deep sequencing on mRNAs isolated from B cells of an independent set of five patients with IgAN and three healthy persons with the same clinical and demographic characteristics. Seventy-seven genes overlapped with 655 differentially regulated genes mentioned above, including 43 up-regulated and thirty-four down-regulated genes. We next investigated whether these genes expression correlated with Gd-IgA1 levels in IgAN patients. Pearson correlation analyses showed PTEN (phosphatase and tensin homolog) was the most powerful gene negatively correlated with Gd-IgA1 levels. CONCLUSIONS: These results demonstrated that dyregulated genes in patients with IgAN were enriched in intestinal immune network for IgA production and autophagy process, and PTEN in B cells might be involved in the mechanism of Gd-IgA1 production.

Pregnancy outcomes in patients with acute kidney injury during pregnancy: a systematic review and meta-analysis.

BACKGROUND: Presently, the matter of pregnancy outcomes of patients with pregnancy related AKI (PR-AKI) were disputed. Thus, we conducted a meta-analysis to evaluate the impact of PR-AKI on pregnancy outcomes. METHOD: We systematically searched MEDLINE, Embase, VIP, CNKI and Wanfang Databases for cohort or case-control studies in women with PR-AKI and those without AKI as a control group to assess the influence of PR-AKI on pregnancy outcomes and kidney outcome. Reduction of odd ratio (OR) was calculated by a random-effects model. RESULTS: One thousand one hundred fifty two articles were systematically reviewed, of those 11 studies were included, providing data of 845 pregnancies in 834 women with PR-AKI and 5387 pregnancies in 5334 women without AKI. In terms of maternal outcomes, women with PR-AKI had a greater likelihood of cesarean delivery (OR, 1.49; 95% confidence interval [CI], 1.37 to 1.61), hemorrhage (1.26; 1.02 to 1.56), HELLP syndrome (1.86; 1.41 to 2.46), placental abruption (3.13; 1.96 to 5.02), DIC (3.41; 2.00 to 5.84), maternal death (4.50; 2.73 to 7.43), but had a lower risk of eclampsia (0.53; 0.34 to 0.83). Women with PR-AKI also had a longer stay in ICU (weighted mean difference, 2.13 day [95% CI 1.43 to 2.83 day]) compared with those without PR-AKI. As for fetal outcomes, higher incidence of stillbirth/perinatal death (3.39, 2.76 to 4.18), lower mean gestational age at delivery (-0.70 week [95% CI -1.21 to -0.19 week]) and lower birth weight (-740 g [95% CI -1180 to 310 g]) were observed in women with PR-AKI. The occurrence of kidney outcome, defined as ESRD requiring dialysis, in women with PR-AKI was 2.4% (95% CI 1.3% to 4.2%). CONCLUSIONS: PR-AKI remains a grave complication and has been associated with increased maternal and fetal mortality.

REDUCTION OF INTRA-ARTICULAR ADHESION BY TOPICAL APPLICATION OF DAIDZEIN FOLLOWING KNEE SURGERY IN RABBITS.

BACKGROUND: Intra-articular adhesion is the commonest complication that is faced by orthopedic surgeons after knee surgery. Thus, the present investigation evaluates the effect of daidzein on intra-articular adhesion in rabbits. MATERIAL AND METHODS: All the rabbits were separated in to four different groups each group carries ten rabbits. Cancellous bone was exposed in each rabbit by removing cortical bone from both side of the femoral condyle. Following daidzein (2.5, 5 and 10 mg/ml) was topically applied for the duration of 10 min to the decorticated areas. Thereafter for the period of 4 week surgical limb was fixed. Effect of daidzein on intra articular adhesion was estimated by visual score through macroscopic examination, histopathology study, hydroxyproline content, fibroblast and collage density. RESULTS: Data obtained in the study suggest that topical application of daidzein (5 and 10 mg/ml) loose the collagen and significantly decreases the adhesion at the decorticated areas. Moreover there were significant reduction in the fibroblast density, hydroxyproline content and optical density of collagen tissue in daidzein (5 and 10 mg/ml) treated group than control. CONCLUSION: Thus present study concludes that topical application of daidzein reduces intra-articular adhesion around the knee.

Correlation between microvascular characteristics and the expression of MVD, IGF-1 and STAT3 in the development of colonic polyps carcinogenesis.

The aim of the present study was to investigate the correlation between vascular characteristics under narrow band imaging (NBI) and the expression of angiogenic factors of colorectal carcinoma and adenoma, and to evaluate the feasibility of NBI in vivo visualizing angiogenesis. Patients with colorectal polyps, which were pathologically confirmed as early carcinoma and adenoma, were recruited and examined by NBI. The vascular pattern was classified into type I (invisible or faintly visible vasculature), type II (clearly visible microvasculature that is regularly arranged in a round, oval honeycomb-like pattern) and type III (clearly visible microvasculature that is irregularly arranged in size and caliber or has irregular winding). Immunohistochemical staining was performed by cluster of differentiation (CD)34, insulin-like growth factor (IGF)-1 and signal transducer and activator of transcription 3 (STAT3). The histological results were compared with the vascular pattern under NBI. Overall, 64 sites (15 adenocarcinomas, 29 adenomas and 20 normal) from 58 patients were recruited in the study and examined by NBI. A higher proportion of adenomas (82.1%, 23/28) and adenocarcinomas (66.7%, 10/15) had vascular patterns II and III, respectively. The expression of microvessel density (MVD)-CD34 and IGF-1 in normal mucosa compared with adenomas and adenocarcinomas was significantly different (P<0.0001 and P=0.0062, respectively). MVD-CD34, IGF-1 and STAT3 expression in the sites displayed with vascular patterns I, II, and III was different significantly (P<0.0001, P=0.0010 and P=0.0055, respectively). The spearman correlation coefficient between NBI vascular pattern and MVD-CD34, IGF-1 and STAT3 expression was 0.67, 0.41 and 0.40, respectively. In conclusion, vascular-pattern analysis and the use of an NBI system may be a promising tool for evaluating angiogenesis of colorectal lesions in real-time endoscopy.

A Systematic Review and Meta-Analysis of Kidney and Pregnancy Outcomes in IgA Nephropathy.

BACKGROUND: The outcomes of pregnancy in immunoglobulin A nephropathy (IgAN) remain controversial. We sought to evaluate the effect of pregnancy on the progression of IgAN as well as the impact of IgAN on pregnancy outcomes. METHODS: We systematically searched MEDLINE, Embase for cohort or case-control studies. OR reductions were calculated with a random-effects model, and kidney outcomes and adverse pregnancy events were analyzed. RESULTS: Our literature search returned 652 relevant articles; 4 studies were included, providing data of 376 pregnancies in 273 patients with IgAN and that of 241 IgAN who did not become pregnant. Four hundred sixty seven patients with chronic kidney disease stages 1-2 were included. Pregnancy in patients with IgAN did not increase the risk of adverse renal events including doubling of serum creatinine, 50% decline in glomerular filtration rate (GFR) and end-stage kidney disease (OR 0.97, 95% CI 0.55-1.70; p = 0.90; I2 = 0.0%, p = 0.79). There was no significant difference in the change in estimated GFR at the end of follow-up in the pregnant and non-pregnant groups (weighted mean difference 0.1 ml/min/1.73 m2 (95% CI -4.85 to 5.04 ml/min/1.73 m2), p = 0.97; I2 = 0%, p = 0.95). Women with IgAN had high rates of infant loss (12.2, 7.4-19.4%), preterm delivery (8.5, 5.9-12.1%), low birth weight (9.5, 6.7-13.3%), and preeclampsia/severe preeclampsia (7.3, 4.9-10.6%). CONCLUSIONS: Pregnancy in IgAN patients with preserved kidney function did not accelerate deterioration of renal function. But pregnant women with IgAN are at higher risk of pregnancy complications.

The role of long-term label-retaining cells in the regeneration of adult mouse kidney after ischemia/reperfusion injury.

BACKGROUND: Label-retaining cells (LRCs) have been recognized as rare stem and progenitor-like cells, but their complex biological features in renal repair at the cellular level have never been reported. This study was conducted to evaluate whether LRCs in kidney are indeed renal stem/progenitor cells and to delineate their potential role in kidney regeneration. METHODS: We utilized a long-term pulse chase of 5-bromo-2'-deoxyuridine (BrdU)-labeled cells in C57BL/6J mice to identify renal LRCs. We tracked the precise morphological characteristics and locations of BrdU(+)LRCs by both immunohistochemistry and immunofluorescence. To examine whether these BrdU(+)LRCs contribute to the repair of acute kidney injury, we analyzed biological characteristics of BrdU(+)LRCs in mice after ischemia/reperfusion (I/R) injury. RESULTS: The findings revealed that the nuclei of BrdU(+) LRCs exhibited different morphological characteristics in normal adult kidneys, including nuclei in pairs or scattered, fragmented or intact, strongly or weakly positive. Only 24.3 ± 1.5 % of BrdU(+) LRCs co-expressed with Ki67 and 9.1 ± 1.4 % of BrdU(+) LRCs were positive for TUNEL following renal I/R injury. Interestingly, we found that newly regenerated cells formed a niche-like structure and LRCs in pairs tended to locate in this structure, but the number of those LRCs was very low. We found a few scattered LRCs co-expressed Lotus tetragonolobus agglutinin (LTA) in the early phase of injury, suggesting differentiation of those LRCs in mouse kidney. CONCLUSIONS: Our findings suggest that LRCs are not a simple type of slow-cycling cells in adult kidneys, indicating a limited role of these cells in the regeneration of I/R injured kidney. Thus, LRCs cannot reliably be considered stem/progenitor cells in the regeneration of adult mouse kidney. When researchers use this technique to study the cellular basis of renal repair, these complex features of renal LRCs and the purity of real stem cells among renal LRCs should be considered.

Curcumin attenuates high glucose-induced podocyte apoptosis by regulating functional connections between caveolin-1 phosphorylation and ROS.

AIM: Caveolin-1 (cav-1) is a major multifunctional scaffolding protein of caveolae. Cav-1 is primarily expressed in mesangial cells, renal proximal tubule cells and podocytes in kidneys. Recent evidence shows that the functional connections between cav-1 and ROS play a key role in many diseases. In this study we investigated whether regulating the functional connections between cav-1 and ROS in kidneys contributed to the beneficial effects of curcumin in treating diabetic nephropathy in vitro and in vivo. METHODS: Cultured mouse podocytes (mpc5) were incubated in a high glucose (HG, 30 mmol/L) medium for 24, 48 or 72 h. Male rats were injected with STZ (60 mg/kg, ip) to induce diabetes. ROS generation, SOD activity, MDA content and caspase-3 activity in the cultured cells and kidney cortex homogenate were determined. Apoptotic proteins and cav-1 phosphorylation were analyzed using Western blot analyses. RESULTS: Incubation in HG-containing medium time-dependently increased ROS production, oxidative stress, apoptosis, and cav-1 phosphorylation in podocytes. Pretreatment with curcumin (1, 5, and 10 µmol/L) dose-dependently attenuated these abnormalities in HG-treated podocytes. Furthermore, in HG-containing medium, the podocytes transfected with a recombinant plasmid GFP-cav-1 Y14F (mutation at a cav-1 phosphorylation site) exhibited significantly decreased ROS production and apoptosis compared with the cells transfected with empty vector. In diabetic rats, administration of curcumin (100 or 200 mg/kg body weight per day, ig, for 8 weeks) not only significantly improved the renal function, but also suppressed ROS levels, oxidative stress, apoptosis and cav-1 phosphorylation in the kidneys. CONCLUSION: Curcumin attenuates high glucose-induced podocyte apoptosis in vitro and diabetic nephropathy in vivo partly through regulating the functional connections between cav-1 phosphorylation and ROS.

Critical role of serum response factor in podocyte epithelial-mesenchymal transition of diabetic nephropathy.

PURPOSE: To investigate the expression and function of serum response factor in podocyte epithelial-mesenchymal transition of diabetic nephropathy. METHODS: The expression of serum response factor, epithelial markers and mesenchymal markers was examined in podocytes or renal cortex tissues following high glucose. Serum response factor was upregulated by its plasmids and downregulated by CCG-1423 to investigate how it influenced podocyte epithelial-mesenchymal transition in diabetic nephropathy. Streptozotocin was used to generate diabetes mellitus in rats. RESULTS: In podocytes after high glucose treatment, serum response factor and mesenchymal markers increased, while epithelial markers declined. Similar changes were observed in vivo. Serum response factor overexpression in podocytes induced expression of Snail, an important transcription factor mediating epithelial-mesenchymal transition. Blockade of serum response factor reduced Snail induction, protected podocytes from epithelial-mesenchymal transition and ameliorated proteinuria. CONCLUSION: Together, increased serum response factor activity provokes podocytes' epithelial-mesenchymal transition and dysfunction in diabetic nephropathy. Targeting serum response factor by small-molecule inhibitor may be an attractive therapeutic strategy for diabetic nephropathy.

Blockade of vascular endothelial growth factor-A/receptor 2 exhibits a protective effect on angiotensin-II stimulated podocytes.

Vascular endothelial growth factor (VEGF) and Angiotensin II (Ang-II) are important in glomerulosclerosis, which is one of the main causes of chronic kidney disease. Previous studies have demonstrated that angiotensin type 1 receptor blocker (ARB) can inhibit the synthesis of VEGF mediated by Ang­II and can effectively treat diabetic nephropathy. In the present study, the expression of VEGF and its receptors (VEGFR1/VEGFR2) was examined in Ang­II stimulated podocytes, which were treated with SU5416, a specific VEGFR2 inhibitor. The protein expression of synaptopodin, VEGFR1/2, phosphorylated VEGFR2 and extracellular signal­regulated kinases (ERK) was assessed by western blot analysis. The mRNA expression of transforming growth factor (TGF)­ß1 was examined by reverse transcription­quantitative polymerase chain reaction. It was observed that Ang­II increased the expression of VEGF­A and VEGFR2. Simultaneously, the increased expression of phosphorylated (p­)VEGFR2 and p­ERK induced by Ang­II was downregulated by SU5416. SU5416 can decrease the expression of synaptopodin and increase the expression of TGF­ß1 induced by Ang­II as well as ARB treatment. The expression of VEGFR1 remained unchanged by either Ang­II or SU5416 treatment. However, the normal podocytes administered SU5416 alone showed low levels of synaptopodin and high expression of TGF­ß1 compared with the control. In conclusion, VEGF­A/VEGFR2 may be essential for podocytes in a normal state. It is suggested that blockade of VEGF­A/VEGFR2 may exhibit a protective effect on Ang-II stimulated podocytes.

Nitro-oleic acid attenuates OGD/R-triggered apoptosis in renal tubular cells via inhibition of Bax mitochondrial translocation in a PPAR-γ-dependent manner.

BACKGROUND: Nitroalkene derivatives of oleic acid (OA-NO2) serve as high-affinity ligand for PPAR-γ, which regulates apoptosis, oxidation and inflammation and plays a central role in ischemia-reperfusion injury. In the present study, we elucidated the protective mechanisms of OA-NO2 against renal ischemia-reperfusion injury. METHODS: HK-2 cells were subjected to oxygen and glucose deprivation followed by re-oxygenation (OGD/R) to mimic renal ischemia-reperfusion injury. Cell apoptosis was analyzed by flow cytometry. Bax mitochondrial translocation, cytochrome c and apoptosis-inducing factor (AIF) cytosolic leakage and Akt/Gsk 3ß phosphorylation were evaluated by Western blotting. Bax activation was visualized by immunocytochemistry. GW9662 and siRNA transfection were employed to examine the involvement of PPAR-γ. RESULTS: OGD/R injury promoted mitochondrial translocation and activation of Bax, leakage of cytochrome c and AIF, subsequent caspase-3 activation, and eventually cell apoptosis. Pre-incubation with OA-NO2 (1.25 µM, 45min) inhibited Bax activation and blocked apoptotic cascade, while the protective effects were negated by GW9662 or PPAR-γ siRNA. Moreover, OA-NO2 restored Akt and Gsk 3ß phosphorylation in a PPAR-γ-dependent way. CONCLUSION: These findings suggest that OA-NO2 attenuates OGD/R-induced apoptosis by inhibiting Bax translocation and activation and the subsequent mitochondria-dependent apoptotic cascade in a PPAR-γ dependent manner.