14-3-3ζ inhibits maladaptive repair in renal tubules by regulating YAP and reduces renal interstitial fibrosis.

Acute kidney injury (AKI) refers to a group of common clinical syndromes characterized by acute renal dysfunction, which may lead to chronic kidney disease (CKD), and this process is called the AKI-CKD transition. The transcriptional coactivator YAP can promote the AKI-CKD transition by regulating the expression of profibrotic factors, and 14-3-3 protein zeta (14-3-3ζ), an important regulatory protein of YAP, may prevent the AKI-CKD transition. We established an AKI-CKD model in mice by unilateral renal ischemia-reperfusion injury and overexpressed 14-3-3ζ in mice using a fluid dynamics-based gene transfection technique. We also overexpressed and knocked down 14-3-3ζ in vitro. In AKI-CKD model mice, 14-3-3ζ expression was significantly increased at the AKI stage. During the development of chronic disease, the expression of 14-3-3ζ tended to decrease, whereas active YAP was consistently overexpressed. In vitro, we found that 14-3-3ζ can combine with YAP, promote the phosphorylation of YAP, inhibit YAP nuclear translocation, and reduce the expression of fibrosis-related proteins. In an in vivo intervention experiment, we found that the overexpression of 14-3-3ζ slowed the process of renal fibrosis in a mouse model of AKI-CKD. These findings suggest that 14-3-3ζ can affect the expression of fibrosis-related proteins by regulating YAP, inhibit the maladaptive repair of renal tubular epithelial cells, and prevent the AKI-CKD transition.

Integrated single-cell and bulk RNA sequencing revealed an epigenetic signature predicts prognosis and tumor microenvironment colorectal cancer heterogeneity.

BACKGROUND: Colorectal cancer (CRC) prognosis prediction is currently a major challenge. Epigenetic regulation has been widely reported for its role in cancer development. AIM: To construct a robust prognostic signature, we used developed and validated across datasets. METHODS: After constructing the signature, the prognostic value of the signature was evaluated in the TCGA cohort and six independent datasets (GSE17526, GSE17537, GSE33113, GSE37892, GSE39048 and GSE39582). The clinical, genomic and transcriptomic features related to the signature were identified. The correlations of the signature score with immune cell infiltration and cell-cell interactions were analyzed. The correlations between the signature score and the sensitivity to different drugs were also predicted. RESULTS: In the TCGA cohort, patients in the low-risk group according to the signature score had longer survival than those in the high-risk group, and this finding was validated in the validation datasets. The signature was a prognostic factor independent of age and sex and was correlated with stage and PD-1/PD-L1 expression. Area under the receiving operating characteristic curve was 0.72. Genomic association analyses revealed that samples from high-risk patients exhibited chromosomal instability. Transcriptomic analyses revealed that the signature score was significantly associated with multiple cellular pathways. Bulk RNA-seq and single-cell sequencing data revealed that the signature reflected differences in infiltrating immune cell-tumor cell interactions, especially for macrophages. The signature also predicted the putative drug sensitivity of CRC samples. CONCLUSION: The signature is a valuable biomarker for predicting CRC prognosis and reflects multiple features of CRC, especially macrophage infiltration in the microenvironment.

Identification of key genes and pathways in diabetic nephropathy by bioinformatics analysis.

AIMS/INTRODUCTION: The aim of the present study was to identify candidate differentially expressed genes (DEGs) and pathways using bioinformatics analysis, and to improve our understanding of the cause and potential molecular events of diabetic nephropathy. MATERIALS AND METHODS: Two cohort profile datasets (GSE30528 and GSE33744) were integrated and used for deep analysis. We sorted DEGs and analyzed differential pathway enrichment. DEG-associated ingenuity pathway analysis was carried out. The screened gene expression feature was verified in the db/db mouse kidney cortex. Then, rat mesangial cells cultured with high-concentration glucose were used for verification. The target genes of transcriptional factor E26 transformation-specific-1 (ETS1) were predicted with online tools and validated using chromatin immunoprecipitation assay quantitative polymerase chain reaction. RESULTS: The two GSE datasets identified 89 shared DEGs; 51 were upregulated; and 38 were downregulated. Most of the DEGs were significantly enriched in cell adhesion, the plasma membrane, the extracellular matrix and the extracellular region. Quantitative reverse transcription polymerase chain reaction analysis validated the upregulated expression of Itgb2, Cd44, Sell, Fn1, Tgfbi and Il7r, and the downregulated expression of Igfbp2 and Cd55 in the db/db mouse kidney cortex. Chromatin immunoprecipitation assay quantitative polymerase chain reaction showed that Itgb2 was the target gene of transcription factor Ets1. ETS1 knockdown in rat mesangial cells decreased integrin subunit beta 2 expression. CONCLUSION: We found that EST1 functioned as an important transcription factor in diabetic nephropathy development through the promotion of integrin subunit beta 2 expression. EST1 might be a drug target for diabetic nephropathy treatment.

Clinicopathological Features of Nondiabetic Renal Diseases from Different Age Groups: An Observational Cross-sectional Study.

BACKGROUND: Diabetes mellitus (DM) has become the leading cause of chronic kidney disease (CKD). Nondiabetic renal diseases (NDRDs) have different clinicopathological features and prognosis from those of diabetic nephropathy. Our study sought to analyze the clinical and pathological features of NDRDs, in different age groups through a cross-sectional study. METHODS: All patients with type 2 DM at our center who underwent renal biopsy between March 1997 and March 2017 were screened and divided into three groups by age: Group 1 (youth group), 18-44 years old; Group 2 (middle-aged group), 45-59 years old; and Group 3 (elderly group), ≥60 years old. We analyzed the clinicopathological data and risk factors by univariate and multivariate logistic regression for NDRD of the patients to identify the features of NDRD in different age groups. RESULTS: We included 982 patients in the final analysis. Patients with NDRD accounted for 64.4% of all patients. IgA nephropathy (IgAN) was the most common pathological pattern in young patients with NDRD, accounting for 26.3%. In the middle-aged group, the two most common pathological patterns were IgAN and membranous nephropathy. Membranous nephropathy was the most common pathological pattern in elderly patients with NDRD, accounting for 29.3%. Consistent with pathological features, glomerular hematuria is a risk factor for NDRD in Group 1 (odds ratio [OR], 26.514; 95% confidence interval [CI], 2.503-280.910; P = 0.006). On the other hand, rapidly increasing proteinuria or nephrotic syndrome is a risk factor for NDRD in Group 2 (OR, 5.921; 95% CI, 2.061-17.013; P = 0.001) and Group 3 (OR, 90.409; 95% CI, 6.198-1318.826; P = 0.001). CONCLUSIONS: This single-center study showed that the proportion and composition of NDRD differ among different age groups. Consistent with pathological features, some clinical indices such as hematuria and proteinuria showed different features among different age groups.