Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. TGF-b1/Smad3 signalling plays a major pathological role in DN; however, the contribution of Smad4 has not been examined. Smad4 depletion in the kidney using anti-Smad4 locked nucleic acid halted progressive podocyte damage and glomerulosclerosis in mouse type 2 DN, suggesting a pathogenic role of Smad4 in podocytes. Smad4 is upregulated in human and mouse podocytes during DN. Conditional Smad4 deletion in podocytes protects mice from type 2 DN, independent of obesity. Mechanistically, hyperglycaemia induces Smad4 localization to mitochondria in podocytes, resulting in reduced glycolysis and oxidative phosphorylation and increased production of reactive oxygen species. This operates, in part, via direct binding of Smad4 to the glycolytic enzyme PKM2 and reducing the active tetrameric form of PKM2. In addition, Smad4 interacts with ATPIF1, causing a reduction in ATPIF1 degradation. In conclusion, we have discovered a mitochondrial mechanism by which Smad4 causes diabetic podocyte injury.
Background: miR-146a has been demonstrated to be involved in normal hematopoiesis and the pathogenesis of many hematological malignancies by inhibiting the expression of its targets. Rs2910164(G>C) may modify the expression of the miR-146a gene, which might influence an individual's predisposition to childhood acute lymphoblastic leukemia (ALL). However, inconsistent findings have been reported on the association between the rs2910164(G>C) polymorphism and the risk of childhood ALL. Methods: A comprehensive meta-analysis was performed to accurately estimate the association between the miR-146a rs2910164 polymorphism and childhood ALL among four different genetic models. Results: This meta-analysis included Asian studies with a total of 1,543 patients and 1,816 controls. We observed a significant difference between patients and controls for the additive model (CC vs. GG: OR = 1.598, 95% CI: 1.003–2.545, P = 0.049) using a random effects model. Meanwhile, there was a trend of increased childhood ALL risk in the dominant model (CC + CG vs. GG: OR = 1.501, 95% CI: 0.976–2.307, P = 0.065), recessive model (CC vs. GG + CG: OR = 1.142, 95% CI: 0.946–1.380, P = 0.168) and allele model (C vs. G: OR = 1.217, 95% CI: 0.987–1.500, P = 0.066) between patients and controls. Conclusions: Our findings suggest that the miR-146a rs2910164 CC genotype was significantly associated with childhood ALL susceptibility.
Bcl2 family proteins play a critical role in cell death or survival. BAX, the death‐promoting protein of bcl2 family, mediated mitochondrial pathway inducing cells’ apoptosis in mammal. MiRNAs have been implicated as negative regulators down‐regulating genes’ expression after post‐transcriptional level. At present, little is known about the regulatory mechanism of miRNA on the Bcl2 family proteins during CyHV‐2 infection in silver crucian carp (Carassius auratus gibelio). In this study, the ccBAX (silver crucian carp BAX) gene was cloned and expressed, and polyclonal antibodies were raised in mouse against the purified ccBAX‐GST fusion protein. The structure analysis indicated that ccBAX protein included four conserve domains (BH1, BH2, BH3 and transmembrane domains) and the expression of ccBAX protein occurred throughout the cells. Furthermore, two miRNAs (miR‐124 and miRNA‐29b) were identified to negatively regulate ccBAX gene expression in GiCF cell. miR‐124 was found to suppress the expression of WT‐ccBAX (wild type), but not the MT‐ccBAX (mutant). Overall, the results demonstrated that the expression of the ccBAX gene was significantly down‐regulated by miR‐124 in silver crucian carp (Carassius auratus gibelio) during CyHV‐2 infection.
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