Influencing factors for postpartum depression in women with gestational diabetes mellitus.

Objective: It remains undefined about the association between gestational diabetes mellitus (GDM) and postpartum depression (PPD). Hence, a cross-sectional study was conducted to evaluate the association between GDM and PPD among pregnant women and to investigate the influencing factors for PPD. Methods: From June 2021 to June 2022, 205 parturients with GDM and 201 without GDM were included in the study as the GDM group and the control group, respectively. The collected data from the general information questionnaire and Self Rating Depression Scale (SDS) were statistically analyzed based on binomial logistic regression analyses and generalized linear mixed models (GLMMs). Results: Age at delivery, gestational age, glycosylated hemoglobin, triglyceride, SDS, and proportions of women who had a history of induced abortion or GDM were significantly different between the GDM group and control group (P<0.05). The incidence of PPD in the GDM group was significantly higher than that in the control group. The neonatal body weight and triglyceride in GDM women with PPD were significantly lower than those in GDM women without PPD (P<0.001). The univariate logistic regression analysis demonstrated that educational age was a protective factor, while glycosylated hemoglobin and GDM were risk factors for PPD. The multiple linear regression analysis revealed that neonatal body weight (OR=-0.904, 95%CI: -1.657 to -0.152, P=0.019) and educational age (OR=-0.166, 95%CI: -0.306 to -0.025, P=0.021) were protective factor, while GDM (OR=1.854, 95%CI: 1.027-2.681, P<0.0001) was a risk factor for PPD. Conclusion: GDM may be associated with PPD. Neonatal body weight and educational age were protective factors for PPD, and GDM was a risk factor for PPD. Therefore, more attention should be paid to the mental health status of women with GDM, especially those with lesser educational age and lower neonatal body weight.

[Application of mRNA nano-delivery system in CAR-T tumor immunotherapy].

Chimeric antigen receptor T cells (CAR-T) immunotherapy, which activates immunity specific to the system in order to achieve antitumor effects, has experienced exciting progress in recent years. mRNA nano-delivery systems, which encapsulate tumor immunotherapy-related antigen mRNA with nanoparticles, have shown great potential in CAR-T tumor immunotherapy. On one hand, these systems can directly target T cells to generate CAR-T cells that directly act upon the corresponding tumor cells. On the other hand, they can be delivered to antigen-presenting cells through targeting, thereby enhancing the function of CAR-T cells and further inducing specific immune responses against tumor cells. This review summarizes the synthesis of mRNA nano-delivery systems and their application in CAR-T tumor immunotherapy.

Young Plasma Attenuated Chronic Kidney Disease Progression after Acute Kidney Injury by Inhibiting Inflammation in Mice.

In the aged patients suffering from acute kidney injury, the risk for progression to chronic kidney disease and mortality is high. Aging accompanied by glomerulosclerosis, interstitial inflammation, and fibrosis might be one of the underlying mechanisms for vulnerability. In addition to sustained activation of the renin-angiotensin system, persistent chronic inflammation with tertiary lymphoid tissue formation is more common and is associated with disease progression in the aged kidney after acute injury. Based on recent laboratory evidence that young blood can rejuvenate the brain, muscle, and heart, we were intrigued by the possible protective effect of young plasma on acute kidney injury in aged mice. Here, we demonstrated that young plasma from 2-month-old mice could attenuate chronic kidney disease progression in 15-month-old mice subjected to acute kidney injury induced by ischemia-reperfusion. In the aged mice after acute kidney injury, young plasma administration decreased tubulointerstitial injury, fibrosis, and tertiary lymphoid tissue formation in kidneys assessed on day 28 after acute injury despite no significant beneficial effect on injury severity and survival. Mechanistically, young plasma inhibited angiotensin II-activated chemokines in pericytes that were responsible for tertiary lymphoid tissue formation. In summary, our data provide evidence that young plasma attenuates the transition from acute kidney injury to chronic kidney disease in aged mice. The therapeutic potential of young plasma infusion or exchange in the aged patients suffering acute kidney injury needs to be addressed in clinical trials.

A correlation analysis on the postpartum anxiety disorder and influencing factors in puerperae with gestational diabetes mellitus.

Objective: The aim of this study is to discuss the postpartum anxiety disorder and influencing factors in puerperae with gestational diabetes mellitus (GDM) to provide a clinical basis for better early identification and intervention of adverse mood. Methods: Convenient sampling method was adopted to investigate 205 pregnant women as the observation group and 201 normal healthy pregnant women in the same period as the control group. The self-rating anxiety scale (SAS) was used to investigate and observe the respondents, evaluate the postpartum anxiety status of patients with GDM, and analyze the related influencing factors. Statistical analysis of the data was performed using SAS 3.0 software. A proposed P < 0.05 was considered as statistically significant. Results: Patients with GDM had a higher risk than normal maternal anxiety, related to years of education, triglycerides, 1-h postprandial blood glucose, and a history of induced abortion. Conclusion: GDM can lead to the occurrence of postpartum anxiety, and the poor psychological state is not conducive to the maternal and infant health. Early identification and early intervention can reduce the harm caused by anxiety and promote the progress of maternal and infant health and clinical research.

Construction of a ferroptosis-related signature based on seven lncRNAs for prognosis and immune landscape in clear cell renal cell carcinoma.

BACKGROUND: Recent studies have demonstrated that long non-coding RNAs (lncRNAs) are involved in regulating tumor cell ferroptosis. However, prognostic signatures based on ferroptosis-related lncRNAs (FRLs) and their relationship to the immune microenvironment have not been comprehensively explored in clear cell renal cell carcinoma (ccRCC). METHODS: In the present study, the expression profiles of ccRCC were acquired from The Cancer Genome Atlas (TCGA) database; 459 patient specimens and 69 adjacent normal tissues were randomly separated into training or validation cohorts at a 7:3 ratio. We identified 7 FRLs that constitute a prognostic signature according to the differential analysis, correlation analysis, univariate regression, and least absolute shrinkage and selection operator (LASSO) Cox analysis. To identify the independence of risk score as a prognostic factor, univariate and multivariate regression analyses were also performed. Furthermore, CIBERSORT was conducted to analyze the immune infiltration of patients in the high-risk and low-risk groups. Subsequently, the differential expression of immune checkpoint and m6A genes was analyzed in the two risk groups. RESULTS: A 7-FRLs prognostic signature of ccRCC was developed to distinguish patients into high-risk and low-risk groups with significant survival differences. This signature has great prognostic performance, with the area under the curve (AUC) for 1, 3, and 5 years of 0.713, 0.700, 0.726 in the training set and 0.727, 0.667, and 0.736 in the testing set, respectively. Moreover, this signature was significantly associated with immune infiltration. Correlation analysis showed that risk score was positively correlated with regulatory T cells (Tregs), activated CD4 memory T cells, CD8 T cells and follicular helper T cells, whereas it was inversely correlated with monocytes and M2 macrophages. In addition, the expression of fourteen immune checkpoint genes and nine m6A-related genes varied significantly between the two risk groups. CONCLUSION: We established a novel FRLs-based prognostic signature for patients with ccRCC, containing seven lncRNAs with precise predictive performance. The FRLs prognostic signature may play a significant role in antitumor immunity and provide a promising idea for individualized targeted therapy for patients with ccRCC.

Effect of Single and Synergistic Reinforcement of PVA Fiber and Nano-SiO2 on Workability and Compressive Strength of Geopolymer Composites.

Geopolymer composites can be used as a proper substitute for ordinary Portland cement, which can reduce carbon dioxide (CO2) emissions and make rational use of industrial waste. In this study, an investigation of the workability and compressive strength of geopolymer composites was carried out through a series of experiments, such as slump flow test, consistency meter test and compressive strength test, to clarify the interaction mechanism among superplasticizer (SP), polyvinyl alcohol (PVA) fiber, Nano-SiO2 (NS) and geopolymer composites, thereby improving the properties of engineered composites. The results showed that with the increase in PVA fiber content, the flowability of geopolymer composites decreased, while the thixotropy increased. With the increase in the NS content, the flowability of geopolymer composites first increased and then decreased, reaching its best at 1.0%, while the thixotropy was the opposite. With the increase in the SP content, the flowability of geopolymer composites increased, while the thixotropy decreased. A significant correlation between thixotropy and flowability of geopolymer composites was found (R2 > 0.85). In addition, the incorporation of single PVA fiber or NS significantly improved the compressive strength of geopolymer composites. Specifically, the compressive strength of geopolymer composites with 0.8% content PVA fiber (60.3 MPa) was 33.4% higher than that without PVA fiber (45.2 MPa), and the compressive strength of geopolymer composites with 1.5% content NS (52.6 MPa) was 16.4% higher than that without NS (45.2 MPa). Considering the synergistic effect, it is found that the compressive strength of geopolymer composites (58.5−63.3 MPa) was significantly higher than that without PVA fiber (45.2−52.6 MPa). However, the flowability and compressive strength of geopolymer composites were only slightly improved compared to that without NS. With the increase in the SP content, the compressive strength of geopolymer composites showed a trend of a slight decrease on the whole. Consequently, the results of this study may be useful for further research in the field of repair and prevention of the delamination of composite structures.

The Synthesis of Conical Carbon.

Conical carbon, specifically multi-walled carbon nanocones (CNCs) and single-walled carboncones, is a new class of sp2 -hybridized carbon allotrope, in addition to fullerene, carbon nanotubes (CNTs), and graphene. Characterized by a conical and delocalized aromatic configuration, the conical carbon structure is considered the intermediate structure between planar graphene and open-cage fullerene. CNCs can be stiffer than CNTs and exhibit intriguing physical and chemical properties owing to their unique hollow conical structure, which make these materials promising for application as field emission sources and scanning probes. The research on conical carbon structures is in its nascent stage, mainly because of the limitations in the synthesis and purification of conical carbons. This review summarizes the significant progress in the synthesis of CNCs and carboncones. Particularly, the synthetic methods, which can be divided into traditional physical-chemical synthesis methods for multi-walled CNCs and emerging bottom-up organic synthesis methods for single-walled carboncones, are comprehensively discussed. In addition, the advantages and disadvantages of the various synthetic methods as well as the possible formation and growth mechanisms of CNCs and carboncones are discussed. Finally, some outlooks on the potential solutions to the synthesis of single-walled carboncones with uniform apex angles are presented.

Identification of miRNA-mRNA network and immune-related gene signatures in IgA nephropathy by integrated bioinformatics analysis.

BACKGROUND: IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, and its diagnosis depends mainly on renal biopsy. However, there is no specific treatment for IgAN. Moreover, its causes and underlying molecular events require further exploration. METHODS: The expression profiles of GSE64306 and GSE93798 were downloaded from the Gene Expression Omnibus (GEO) database and used to identify the differential expression of miRNAs and genes, respectively. The StarBase and TransmiR databases were employed to predict target genes and transcription factors of the differentially expressed miRNAs (DE-miRNAs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to predict biological functions. A comprehensive analysis of the miRNA-mRNA regulatory network was constructed, and protein-protein interaction (PPI) networks and hub genes were identified. CIBERSORT was used to examine the immune cells in IgAN, and correlation analyses were performed between the hub genes and infiltrating immune cells. RESULTS: Four downregulated miRNAs and 16 upregulated miRNAs were identified. Forty-five and twelve target genes were identified for the upregulated and downregulated DE-miRNAs, respectively. CDKN1A, CDC23, EGR1, HIF1A, and TRIM28 were the hub genes with the highest degrees of connectivity. CIBERSORT revealed increases in the numbers of activated NK cells, M1 and M2 macrophages, CD4 naive T cells, and regulatory T cells in IgAN. Additionally, HIF1A, CDC23, TRIM28, and CDKN1A in IgAN patients were associated with immune cell infiltration. CONCLUSIONS: A potential miRNA-mRNA regulatory network contributing to IgAN onset and progression was successfully established. The results of the present study may facilitate the diagnosis and treatment of IgAN by targeting established miRNA-mRNA interaction networks. Infiltrating immune cells may play significant roles in IgAN pathogenesis. Future studies on these immune cells may help guide immunotherapy for IgAN patients.

NCR3LG1 (B7-H6) is a potential prognostic factor for bladder cancer patients.

BACKGROUND: NCR3LG1 (B7-H6) protein is selectively overexpressed on tumour and is associated with fatal disease progression of various cancer. However, its prognostic value in bladder cancer (BCa) has not been well elaborated. METHODS: We examined the expression of NCR3LG1 in human BCa and analysed its clinical significance and prognostic value. Meanwhile, the expression of NCR3LG1 was intervened in human BCa cell line 253JBV to analyse subsequent effects on tumour. RESULTS: According to TCGA data, the disease-free survival rate was statistically significant between the NCR3LG1 high expression group and the low expression group (Log Rank p = 0.006). Immunohistochemical staining showed that the expression of NCR3LG1 in BCa tissue was significantly higher than that in adjacent tissues (p < 0.0001), which was positively correlated with TNM staging (p = 0.008), histological grade (p = 0.022), and lymphoma metastasis of BCa (p = 0.032). The proliferation (p < 0.0001), invasion (p < 0.001) and migration ability (p < 0.001) of 253JBV cells are significantly inhibited by knocking down the expression of NCR3LG1, and the cell cycle arrest is induced at the G1 phase, which accelerates the apoptosis of BCa cells (p < 0.005). CONCLUSION: Our findings indicate that NCR3LG1 is involved in the progression of human BCa and may become a potential prognostic biomarker for BCa.

Methylation in pericytes after acute injury promotes chronic kidney disease.

The origin and fate of renal myofibroblasts is not clear after acute kidney injury (AKI). Here, we demonstrate that myofibroblasts were activated from quiescent pericytes (qPericytes) and the cell numbers increased after ischemia/reperfusion injury-induced AKI (IRI-AKI). Myofibroblasts underwent apoptosis during renal recovery but one-fifth of them survived in the recovered kidneys on day 28 after IRI-AKI and their cell numbers increased again after day 56. Microarray data showed the distinctive gene expression patterns of qPericytes, activated pericytes (aPericytes, myofibroblasts), and inactivated pericytes (iPericytes) isolated from kidneys before, on day 7, and on day 28 after IRI-AKI. Hypermethylation of the Acta2 repressor Ybx2 during IRI-AKI resulted in epigenetic modification of iPericytes to promote the transition to chronic kidney disease (CKD) and aggravated fibrogenesis induced by a second AKI induced by adenine. Mechanistically, transforming growth factor-ß1 decreased the binding of YBX2 to the promoter of Acta2 and induced Ybx2 hypermethylation, thereby increasing α-smooth muscle actin expression in aPericytes. Demethylation by 5-azacytidine recovered the microvascular stabilizing function of aPericytes, reversed the profibrotic property of iPericytes, prevented AKI-CKD transition, and attenuated fibrogenesis induced by a second adenine-AKI. In conclusion, intervention to erase hypermethylation of pericytes after AKI provides a strategy to stop the transition to CKD.

Rejuvenation: Turning back the clock of aging kidney.

Aging is inevitable in life. It is defined as impaired adaptive capacity to environmental or internal stresses with growing rates of disease and death. Aging is also an important risk factor for various kidney diseases such as acute kidney injury and chronic kidney disease. Patients older than 65 years have nearly 28% risk of failing recovery of kidney function when suffering from acute kidney injury. It is reported that more than a third of population aged 65 years and older have chronic kidney disease in Taiwan, and the occurrence of multiple age-related disorders is predicted to increase in parallel. Renal aging is a complex, multifactorial process characterized by many anatomical and functional changes. Several factors are involved in renal aging, such as loss of telomeres, cell cycle arrest, chronic inflammation, activation of renin-angiotensin system, decreased klotho expression, and development of tertiary lymphoid tissues. These changes can also be observed in many other different types of renal injury. Recent studies suggested that young blood may rejuvenate aged organs, including the kidneys. In order to develop new therapeutic strategies for renal aging, the mechanisms underlying renal aging and by which young blood can halt or reverse aging process warrants further study.

Urine anti-PLA2R antibody is a novel biomarker of idiopathic membranous nephropathy.

Since urine samples more directly reflect kidney alterations and damage than blood samples, we investigated whether urine anti-PLA2R antibody (uPLA2R-Ab) could be utilized similarly to serum anti-PLA2R antibody (sPLA2R-Ab) as a noninvasive biomarker of idiopathic membranous nephropathy (IMN). In this study, we performed a qualitative analysis using an indirect immunofluorescence test (IIFT) and measured uPLA2R-Ab and sPLA2R-Ab concentrations using an enzyme-linked immunosorbent assay (ELISA) in 28 patients with biopsy-proven IMN and 12 patients with secondary membranous nephropathy (SMN). Overall, 64.3% (n=18) of patients with IMN had IIFT-positive sPLA2R-Ab, 67.9% (n=19) of patients with IMN had IIFT-positive uPLA2R-Ab, and none of the SMN patients had IIFT-positive sPLA2R-Ab or uPLA2R-Ab. The titers of the anti-PLA2R antibody from the IMN patients in the urine (10.72±22.24 RU/µmol, presented as uPLA2R-Ab/urine creatinine) and serum (107.36±140.93 RU/ml) were higher than those from the SMN patients (0.51±0.46 RU/µmol, 0.008±0.029 RU/ml, respectively, p<0.05). Statistical analyses indicated that there were positive correlations between uPLA2R-Ab and gPLA2R, sPLA2R-Ab or urinary protein and negative correlations between uPLA2R-Ab and serum albumin in patients with IMN. In conclusion, uPLA2R-Ab is a novel biomarker of IMN. sPLA2R-Ab combined with uPLA2R-Ab might be more helpful for diagnosis and activity in PLA2R associated MN.

Multiple Mechanisms are Involved in Salt-Sensitive Hypertension-Induced Renal Injury and Interstitial Fibrosis.

Salt-sensitive hypertension (SSHT) leads to kidney interstitial fibrosis. However, the potential mechanisms leading to renal fibrosis have not been well investigated. In present study, Dahl salt-sensitive (DS) rats were divided into three groups: normal salt diet (DSN), high salt diet (DSH) and high salt diet treated with hydrochlorothiazide (HCTZ) (DSH + HCTZ). A significant increase in systolic blood pressure (SBP) was observed 3 weeks after initiating the high salt diet, and marked histological alterations were observed in DSH rats. DSH rats showed obvious podocyte injury, peritubular capillary (PTC) loss, macrophage infiltration, and changes in apoptosis and cell proliferation. Moreover, Wnt/ß-catenin signaling was significantly activated in DSH rats. However, HCTZ administration attenuated these changes with decreased SBP. In addition, increased renal and urinary Wnt4 expression was detected with time in DSH rats and was closely correlated with histopathological alterations. Furthermore, these alterations were also confirmed by clinical study. In conclusion, the present study provides novel insight into the mechanisms related to PTC loss, macrophage infiltration and Wnt/ß-catenin signaling in SSHT-induced renal injury and fibrosis. Therefore, multi-target therapeutic strategies may be the most effective in preventing these pathological processes. Moreover, urinary Wnt4 may be a noninvasive biomarker for monitoring renal injury after hypertension.

Wnt4 is a novel biomarker for the early detection of kidney tubular injury after ischemia/reperfusion injury.

Earlier intervention after acute kidney injury would promote better outcomes. Our previous study found that Wnt proteins are promptly upregulated after ischemic kidney injury. Thus, we assessed whether Wnt4 could be an early and sensitive biomarker of tubular injury. We subjected mice to bilateral ischemia/reperfusion injury (IRI). Kidney and urinary Wnt4 expression showed an early increase at 3 hours and increased further at 24 hours post-IRI and was closely correlated with histopathological alterations. Serum creatinine slightly increased at 6 hours, indicating that it was less sensitive than Wnt4 expression. These data were further confirmed by clinical study. Both kidney and urinary Wnt4 expression were significantly increased in patients diagnosed with biopsy-proven minimal change disease (MCD) with tubular injury, all of whom nevertheless had normal estimated glomerular filtration rate (eGFR) and serum creatinine. The increased Wnt4 expression also strongly correlated with histopathological alterations in these MCD patients. In conclusion, this is the first demonstration that increases in both kidney and urinary Wnt4 expression can be detected more sensitively and earlier than serum creatinine after kidney injury. In particular, urinary Wnt4 could be a potential noninvasive biomarker for the early detection of tubular injury.

Serum Anti-PLA2R Antibody Predicts Treatment Outcome in Idiopathic Membranous Nephropathy.

BACKGROUND: M-type phospholipase A2 receptor (PLA2R) has been identified as the major target antigen in idiopathic membranous nephropathy (IMN). However, the role of glomerular PLA2R (gPLA2R) and the associations of serum anti-PLA2R antibody (sPLA2R-Ab) titre with diagnosis, treatment and prognosis in IMN need to be further investigated. METHODS: We screened 148 consecutive patients with biopsy-proven membranous nephropathy (MN; 113 with IMN and 35 with secondary MN (SMN)) who were followed up for ≤20 months. Serum and urine samples were simultaneously collected at different time points. The levels of sPLA2R-Ab were detected using immunofluorescence and enzyme-linked immunosorbent assay. gPLA2R was assessed by immunofluorescence. RESULTS: Most patients with IMN displayed both gPLA2R and sPLA2R-Ab positive (85.8 and 82.3%, respectively). In contrast, very few patients with SMN showed either gPLA2R or sPLA2R-Ab positive. The sPLA2R-Ab titre, not gPLA2R, was significantly correlated with proteinuria. Surprisingly, changes in sPLA2R-Ab titre occurred earlier and faster than proteinuria in patients who were followed up for ≤20 months during the whole period of observation. Survival analysis of IMN patients indicated a significant association between sPLA2R-Ab titre and outcome, whereas, no significant difference was observed between the gPLA2R intensity and outcome. CONCLUSIONS: These data indicate that sPLA2R-Ab might be a better biomarker for IMN diagnosis and treatment outcome. In addition, monitoring sPLA2R-Ab titre may assist in determining when to initiate the administration of immunosuppressive agents and in evaluating treatment efficacy.

Overexpression of Heme Oxygenase-1 Prevents Renal Interstitial Inflammation and Fibrosis Induced by Unilateral Ureter Obstruction.

Renal fibrosis plays an important role in the onset and progression of chronic kidney diseases. Many studies have demonstrated that heme oxygenase-1 (HO-1) is involved in diverse biological processes as a cytoprotective molecule, including anti-inflammatory, anti-oxidant, anti-apoptotic, antiproliferative, and immunomodulatory effects. However, the mechanisms of HO-1 prevention in renal interstitial fibrosis remain unknown. In this study, HO-1 transgenic (TG) mice were employed to investigate the effect of HO-1 on renal fibrosis using a unilateral ureter obstruction (UUO) model and to explore the potential mechanisms. We found that HO-1 was adaptively upregulated in kidneys of both TG and wild type (WT) mice after UUO. The levels of HO-1 mRNA and protein were increased in TG mice compared with WT mice under normal conditions. HO-1 expression was further enhanced after UUO and remained high during the entire experimental process. Renal interstitial fibrosis in the TG group was significantly attenuated compared with that in the WT group after UUO. Moreover, overexpression of HO-1 inhibited the loss of peritubular capillaries. In addition, UUO-induced activation and proliferation of myofibroblasts were suppressed by HO-1 overexpression. Furthermore, HO-1 restrained tubulointerstitial infiltration of macrophages and regulated the secretion of inflammatory cytokines in UUO mice. We also found that high expression of HO-1 inhibited reactivation of Wnt/ß-catenin signaling, which could play a crucial role in attenuating renal fibrosis. In conclusion, these data suggest that HO-1 prevents renal tubulointerstitial fibrosis possibly by regulating the inflammatory response and Wnt/ß-catenin signaling. This study provides evidence that augmentation of HO-1 levels may be a therapeutic strategy against renal interstitial fibrosis.

Comparison of different therapies in high-risk patients with idiopathic membranous nephropathy.

BACKGROUND/PURPOSE: Immunosuppressive therapy plays an important role in patients with high-risk idiopathic membranous nephropathy (IMN), but the therapeutic modality is still controversial. METHODS: Corticosteroid combined with oral tacrolimus (TAC, target trough blood concentration of 4-8 ng/mL), intravenous cyclophosphamide (CYC, 750 mg/m(2)/mo, or oral mycophenolate mofetil (MMF, 1.5-2.0 g/d) were randomly administered for 9 months to 90 patients with IMN proved with renal biopsy with severe proteinuria (>8 g/d). RESULTS: Eighty-six of the 90 patients completed the study. The total remission (TR) rates in the TAC group were significantly higher than those in the CYC group at 1 and 2 months (p < 0.01) and the MMF group at 1-4 months (p < 0.01). The TR rates were 83.3%, 73.3%, and 70.0% in the TAC, CYC, and MMF groups at 9 months (p = 0.457), and there were no significant differences between the three groups from 5 to 9 months. Furthermore, TAC reduced proteinuria and ameliorated hypoalbuminemia more quickly and effectively than CYC and MMF. We observed no severe adverse events in the three groups. CONCLUSION: Tacrolimus combined with corticosteroid had tolerable adverse effects and induced the remission of IMN more effectively and more rapidly. This is the first prospective randomized cohort study to compare three different therapies in patients at high risk for IMN. It provides strong evidence for choosing optimal treatment for patients with IMN. The long-term efficacy of this treatment strategy should be investigated further in future studies.

Angiopoietin-Like-4, a Potential Target of Tacrolimus, Predicts Earlier Podocyte Injury in Minimal Change Disease.

Podocyte injury plays central roles in proteinuria and kidney dysfunction, therefore, identifying specific biomarker to evaluate earlier podocyte injury is highly desirable. Podocyte-secreted angiopoietin-like-4 (Angptl4) mediates proteinuria in different types of podocytopathy. In the present study, we established an experimental minimal change disease (MCD) rat model, induced by adriamycin (ADR) and resulted in definite podocyte injury, to identify the dynamic changes in Angptl4 expression. We also investigated the direct effects of tacrolimus on Angptl4 and podocyte repair. We determined that the glomerular Angptl4 expression was rapidly upregulated and reached a peak earlier than desmin, an injured podocyte marker, in the ADR rats. Furthermore, this upregulation occurred prior to heavy proteinuria and was accompanied by increased urinary Angptl4. We observed that the Angptl4 upregulation occurred only when podocyte was mainly damaged since we didn't observe little Angptl4 upregulation in MsPGN patients. In addition, we observed the glomerular Angptl4 mainly located in injured podocytes rather than normal podocytes. Moreover, we found that tacrolimus treatment significantly promoted podocyte repair and reduced glomerular and urinary Angptl4 expression at an earlier stage with a significant serum Angptl4 upregulation. And similar results were confirmed in MCD patients. In conclusion, this study represents the first investigation to demonstrate that Angptl4 can predict podocyte injury at earlier stages in MCD and the identification of earlier podocyte injury biomarkers could facilitate the prompt diagnosis and treatment of patients with podocytopathy, as well as determination of the prognosis and treatment efficacy in these diseases.

The administration of erythropoietin attenuates kidney injury induced by ischemia/reperfusion with increased activation of Wnt/ß-catenin signaling.

BACKGROUND/PURPOSE: Understanding the mechanisms of protecting the kidneys from injury is of great importance because there are no effective therapies that promote repair and the kidneys frequently do not repair adequately. Evidence has shown that erythropoietin (EPO) has a vital renoprotective role, independent of its erythropoietic effect. However, whether EPO can contribute to kidney repair after injury and the potential mechanisms are not fully understood. METHODS: To investigate the renoprotective mechanism of EPO, a kidney ischemia/reperfusion injury (IRI) model was induced in adult male Sprague-Dawley rats. The rats were subsequently randomly treated with EPO or a vehicle 6 hours after the kidney IRI. The rats were sacrificed on Day 3, Day 5, and Day 7 post kidney IRI. Renal function and histological alterations were examined. Renal interstitial macrophage infiltration, cell proliferation, apoptosis, and angiogenesis were evaluated by immunostaining. Furthermore, the effects of EPO on the Wnt/ß-catenin pathway and IRI-related micro-RNAs were investigated. RESULTS: The administration of EPO significantly improved renal function and reduced tubular injury. Furthermore, EPO treatment significantly prevented tubular cell apoptosis and promoted cell proliferation after IRI. Erythropoietin significantly suppressed macrophage infiltration, compared to the vehicle. In addition, treatment with EPO markedly prevented the loss of microvasculature. We have also demonstrated that, compared to the vehicle, EPO administration enhanced the expression of Wnt7b and ß-catenin, and downregulated miR-21, -214, -210, and -199a. CONCLUSION: Erythropoietin protects the kidneys against IRI by attenuating injury of the renal microvasculature and tubule epithelial cells, by promoting Wnt/ß-catenin pathway activation, and by regulating miRNA expression.

Upregulation of podocyte-secreted angiopoietin-like-4 in diabetic nephropathy.

Podocyte injury plays a key role in the development of diabetic nephropathy (DN). Understanding the changes in podocyte structure and function in diabetes mellitus may lead to novel diagnostic tools and treatment strategies for DN. Albuminuria, histological alterations, and podocyte injury were detected at different time points in streptozotocin (STZ)-induced diabetic rats. Increased urinary albumin-to-creatinine ratios (ACR) and podocyte injury were significantly observed 4 weeks post-STZ injection. We determined the glomerular expression and distribution of angiopoietin-like 4 (Angptl4) by immunofluorescence and real-time PCR. Glomerular Angptl4 expression was mostly colocalized with synaptopodin, a podocyte marker, with substantial additional overlap with the glomerular basement membrane (GBM). This finding indicated that Angptl4 might be primarily secreted by podocytes and moved toward the GBM. Moreover, we observed by Western blot analysis and ELISA that the urinary Angptl4 level was gradually upregulated in both STZ-induced rats and diabetic patients with microalbuminuria and macroalbuminuria. We further found that the increased glomerular Angptl4 expression was closely related to the urinary ACR level and podocyte injury. In addition, the urinary Angptl4 expression was closely associated with albuminuria in the rats and patients with DN. This study is the first to show that podocyte-secreted Angptl4 is upregulated in DN and can be detected in urine. Angptl4 might function as a podocyte injury marker and could be a potential and novel diagnostic and therapeutic biomarker for DN.