MicroRNAs (miRNAs) possess an important regulating effect among numerous renal diseases, while their functions in the process of epithelial-to-mesenchymal transition (EMT) after podocyte injury remain unclear. The purpose of our study is to identify the potential functions of miR-30a in EMT of podocytes and explore the underlying mechanisms of miR-30a in the impaired podocytes. The results revealed that downregulation of miR-30a in podocyte injury animal models and patients, highly induced the mesenchymal markers of EMT including Collagen I, Fibronectin and Snail. Furthermore, overexpression of miR-30a enhances epithelial markers (E-cadherin) but diminished mesenchymal markers (Collagen I, Fibronectin and Snail) in podocytes. In addition, we established miR-30a target NFATc3, an important transcription factor of Non-canonical Wnt signaling pathway. More importantly, our findings demonstrated that the augmentation of miR-30a level in podocytes inhibits the nuclear translocation of NFATc3 to protect cytoskeleton disorder or rearrangement. In summary, we uncovered the protective function of miR30a targeting NFATc3 in the regulation of podocyte injury response to EMT.
Nephron progenitor cells surround around the ureteric bud tips (UB) and inductively interact with the UB to originate nephrons, the basic units of renal function. This process is determined by the internal balance between self-renewal and consumption of the nephron progenitor cells, which is depending on the complicated regulation networks. It has been reported that Zeb1 regulates the proliferation of mesenchymal cells in mouse embryos. However, the role of Zeb1 in nephrons generation is not clear, especially in metanephric mesenchyme (MM). Here, we detected cell proliferation, apoptosis and migration in MM cells by EdU assay, flow cytometry assay and wound healing assay, respectively. Meanwhile, Western and RT-PCR were used to measure the expression level of Zeb1 and Six2 in MM cells and developing kidney. Besides, the dual-luciferase assay was conducted to study the molecular relationship between Zeb1 and Six2. We found that knock-down of Zeb1 decreased cell proliferation, migration and promoted cell apoptosis in MM cells and Zeb1 overexpression leaded to the opposite data. Western-blot and RT-PCR results showed that knock-down of Zeb1 decreased the expression of Six2 in MM cells and Zeb1 overexpression contributed to the opposite results. Similarly, Zeb1 promoted Six2 promoter reporter activity in luciferase assays. However, double knock-down of Zeb1 and Six2 did not enhance the apoptosis of MM cells compared with control cells. Nevertheless, double silence of Zeb1 and Six2 repressed cell proliferation. In addition, we also found that Zeb1 and Six2 had an identical pattern in distinct developing phases of embryonic kidney. These results indicated that there may exist a complicated regulation network between Six2 and Zeb1. Together, we demonstrate Zeb1 promotes proliferation and apoptosis and inhibits the migration of MM cells, in association with Six2.
The transcriptional repressor cAMP response element modulator (CREM) has an important role in T-cell development. In this study, we used the integrated Bioinformatics Methods to explore the role of CREM in gastric adenocarcinoma (GAC). Our results showed that high CREM expression was closely related with poorer overall survival in GAC. By GSEA cluster analysis, we found that the high expression of CREM was associated with the cancer-associated pathway in GAC. Moreover, single-cell sequencing data showed that CREM is mainly localized in exhausted CD8+ T cells. Its prognostic value and the potential function lead to T-cell exhaustion in the tumor microenvironment (TME). Similar results were also obtained in glioma and lung cancer. High expression of CREM, correlated with clinical relevance of GAC, was associated with T-cell exhaustion and M2 polarization in GAC. These findings suggest that CREM can be used as a prognostic biomarker in GAC, which might provide a novel direction to explore the pathogenesis of GAC.
Curcumin, the primary bioactive component isolated from turmeric, has been found to possess a variety of biological functions, including anti-leukemia activity. However, the effect of curcumin in different leukemia cells vary. In this study, we demonstrated that curcumin induced the expression of AIM2, IFI16, and NLRC4 inflammasomes in leukemia cells U937 by increasing the expression levels of ISG3 transcription factor complex, which activated caspase 1, promoted cleavage of GSDMD, and induced pyroptosis. We also found that pyroptosis executor GSDMD was not expressed in two curcumin-insensitive cells HL60 and K562 cells. In addition, exogenous overexpression of GSDMD by lentiviral transduction in K562 cells increased the anti-cancer activity of curcumin, and inhibiting the expression of GSDMD by shRNA enhanced U937 cells to resist curcumin. The results showed that inducing pyroptosis is a novel mechanism underlying the anti-leukemia effects of curcumin.
Accumulating evidence demonstrated that miRNAs are highly involved in kidney fibrosis and Epithelial-Eesenchymal Transition (EMT), however, the mechanisms of miRNAs in kidney fibrosis are poorly understood. In this work, we identified that miR542-3p could promote EMT through down-regulating bone morphogenetic protein 7 (BMP7) expression by targeting BMP7 3′UTR. Firstly, real-time PCR results showed that miR542-3p was significantly up-regulated in kidney fibrosis in vitro and in vivo. Moreover, Western blot results demonstrated that miR542-3p may promote EMT in the NRK52e cell line. In addition, we confirmed that BMP7, which played a crucial role in anti-kidney fibrosis and suppressed the progression of EMT, was a target of miR542-3p through Dual-Luciferase reporter assay, as did Western blot analysis. The effects of miR542-3p on regulating EMT could also be suppressed by transiently overexpressing BMP7 in NRK52e cells. Taken together, miR542-3p may be a critical mediator of the induction of EMT via directly targeting BMP7.
Osteoporosis (OP) is an increasing public health problem worldwide. Genetic factors are considered to be major contributors to the pathogenesis of OP. The aim of this study was to investigate the association of the purinergic P2X7 receptor (P2X7R) and estrogen receptor-α (ER-α) genes with OP risk, and the effect of the possible interaction between the two genes on predisposition to OP in Chinese postmenopausal women. A total of 596 subjects, including 350 OP patients and 246 controls, were recruited in this case-control study. Five functional single-nucleotide polymorphisms (SNPs) in the P2X7R gene (rs2393799, rs7958311, rs1718119, rs2230911, rs3751143) and two ER-α PvuII and XbaI polymorphisms were genotyped and analyzed. Single-gene variant analysis showed that the carriers of the CC genotype of P2X7R rs3751143 revealed an increased OP risk. Haplotype rs1718119G-rs2230911G-rs3751143C also appeared to be a significant 'risk' haplotype with OP. For the ER-α gene, no evidence of significant association of PvuII or XbaI polymorphism with OP risk was found. Moreover, there was a significant gene-gene interaction between P2X7R rs3751143 and ER-α PvuII; the cross-validation consistency was 10/10 and the testing accuracy was 0.5818 (P = 0.0107). A 1.67-fold-increased risk for OP was detected in individuals carrying the genotypes of AC or CC of rs3751143 and Pp or PP of PvuII compared to subjects with AA of rs3751143 and pp of PvuII. Our findings suggest an important association of the P2X7R rs3751143CC genotype and the rs1718119G-rs2230911G-rs3751143C haplotype with an increased OP risk. Also, the P2X7R rs3751143 and ER-α PvuII two-locus interaction confers a significantly high susceptibility to OP in Chinese postmenopausal women.
Apobec-1 complementation factor (A1CF) is a member of the heterogeneous nuclear ribonucleoproteins (hnRNP) family, which participates in site-specific posttranscriptional RNA editing of apolipoprotein B (apoB) transcript. The posttranscriptional editing of apoB mRNA by A1CF in the small intestine is required for lipid absorption. Apart from the intestine, A1CF mRNA is also reported to be highly expressed in the kidneys. However, it is remained unknown about the functions of A1CF in the kidneys. The aim of this paper is to explore the potential functions of A1CF in the kidneys. Our results demonstrated that in C57BL/6 mice A1CF was weakly expressed in embryonic kidneys from E15.5dpc while strongly expressed in mature kidneys after birth, and it mainly existed in the tubules of inner cortex. More importantly, we identified A1CF negatively regulated the process of epithelial-mesenchymal transition (EMT) in kidney tubular epithelial cells. Our results found ectopic expression of A1CF up-regulated the epithelial markers E-cadherin, and down-regulated the mesenchymal markers vimentin and α-smooth muscle actin (α-SMA) in NRK52e cells. In addition, knockdown of A1CF enhanced EMT contrary to the overexpression effect. Notably, the two A1CF variants led to the similar trend in the EMT process. Taken together, these data suggest that A1CF may be an antagonistic factor to the EMT process of kidney tubular epithelial cells.
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