Renal ischemia/reperfusion (I/R), a major cause of acute kidney injury (AKI), is a serious clinical event in patients during post-renal transplantation. I/R is associated with renal dysfunction and tubular apoptosis, and calcium (Ca2+) overload has been reported to be a crucial factor on tubular apoptosis in I/R injury (IRI). The canonical transient receptor potential channel 6 (TRPC6), a type of non-selective Ca2+ channel, is involved in many renal diseases. Our earlier study identified that TRPC6-mediated Ca2+ influx plays a novel role in suppressing cytoprotective autophagy triggered by oxidative stress in primary tubular epithelial cells (TECs). This study explored the potential beneficial impact of TRPC6 knockout (TRPC6−/−) and the relevant cellular mechanisms against I/R-induced AKI in mice. Measuring changes of renal function, apoptotic index, and autophagy in mouse kidneys that suffered 24 h reperfusion after 40 min ischemia and working in vitro with TECs that suffered 24 h reoxygenation after 24 h hypoxia, we found that 1) IRI tissues had increased TRPC6 expression and TRPC6 knockout significantly ameliorated renal damage induced by IRI; 2) TRPC6 knockout enhanced the level of autophagy and alleviated the depolarization of mitochondrial membrane potential (ψm, MMP) and apoptotic changes upon IRI; and 3) IRI tissues had increased p-AKT and p-ERK1/2 expressions, while TRPC6 knockout could markedly reduce the phosphorylation of AKT and ERK1/2. These discoveries suggest that, by reducing Ca2+ overload, the underlying protective mechanism of TRPC6−/− may be involved in down-regulation of PI3K/AKT and ERK signaling, which is likely to provide a new avenue for future AKI therapies.
Kidney fibrosis is generally confirmed to have a significant role in chronic kidney disease, resulting in end-stage kidney failure. Epithelial–mesenchymal transition (EMT) is an important molecular mechanism contributing to fibrosis. Tubular epithelial cells (TEC), the major component of kidney parenchyma, are vulnerable to different types of injuries and are a significant source of myofibroblast by EMT. Furthermore, TRPC6 knockout plays an anti-fibrotic role in ameliorating kidney damage. However, the relationship between TRPC6 and EMT is unknown. In this study, TRPC6−/− and wild-type (WT) mice were subjected to a unilateral ureteric obstruction (UUO) operation. Primary TEC were treated with TGF-β1. Western blot and immunofluorescence data showed that fibrotic injuries alleviated with the inhibition of EMT in TRPC6−/− mice compared to WT mice. The activation of AKT-mTOR and ERK1/2 pathways was down-regulated in the TRPC6−/− mice, while the loss of Na+/K+-ATPase and APQ1 was partially recovered. We conclude that TRPC6 knockout may ameliorate kidney fibrosis by inhibition of EMT through down-regulating the AKT-mTOR and ERK1/2 pathways. This could contribute to the development of effective therapeutic strategies on chronic kidney diseases.
Background/Aims: Photodynamic therapy (PDT) is a promising noninvasive technique, which has been successfully applied to the treatment of human cancers. Studies have shown that the Bcl-2 family proteins play important roles in PDT-induced apoptosis. However, whether Bcl-2-interacting mediator of cell death (Bim) is involved in photodynamic treatment remains unknown. In this study, we attempt to determine the effect of Bim on Photofrin photodynamic treatment (PPT)-induced apoptosis in human lung adenocarcinoma ASTC-a-1 cells. Methods: The translocation of Bim/Bax of the cells were monitored by laser confocal scanning microscope. The levels of Bim protein and activated caspase-3 in cells were detected by western blot assay. Caspase-3 activities were measured by Caspase-3 Fluorogenic Substrate (Ac-DEVD-AFC) analysis. The induction of apoptosis was detected by Hoechst 33258 and PI staining as well as flow cytometry analysis. The effect of Bim on PPT-induced apoptosis was determined by RNAi. Results: BimL translocated to mitochondria in response to PPT, similar to the downstream pro-apoptotic protein Bax activation. PPT increased the level of Bim and activated caspase-3 in cells and that knockdown of Bim by RNAi significantly protected against caspase-3 activity. PPT-induced apoptosis were suppressed in cells transfected with shRNA-Bim. Conclusion: We demonstrated the involvement of Bim in PPT-induced apoptosis in human ASTC-a-1 lung adenocarcinoma cells and suggested that enhancing Bim activity might be a potential strategy for treating human cancers.
The hippocampus is located in the limbic system and is vital in learning ability, memory formation and emotion regulation, and is associated with depression, epilepsy and mental retardation in an abnormal developmental situation. Several factors have been found to modulate the development of the hippocampus, and epigenetic modification have a crucial effect in this progress. The present review summarizes the epigenetic modifications, including DNA methylation, histone acetylation, and non-coding RNAs, regulating all stages of hippocampal development, focusing on the growth of Ammon's horn and the dentate gyrus in humans and rodents. These modifications may significantly affect hippocampal development and health in addition to cognitive processes. Contents 1. Introduction 2. Development of the hippocampus 3. Epigenetic modifications in hippocampal development 4. Conclusions
Prenatal nicotine exposure (PNE) is closely related to depression in offspring. However, the underlying mechanism is still unclear. We hypothesized that neurosteroid in the hippocampus may mediate PNE-induced depression-like behaviors. Nicotine was subcutaneously administered (1.0 mg/kg) to pregnant rats twice daily from gestational day (GD) 9 to 20. In adolescent offspring, PNE significantly increased immobility time and decreased the sucrose preference in female rats. The numbers of hippocampal neurons declined in the CA3 and DG regions. Steroidogenic acute regulatory protein (StAR) expression was suppressed in female rats. In fetal offspring, the neuronal numbers of CA3 regions in PNE female fetal hippocampal were significantly decreased, accompanied by the enhanced content of corticosterone and StAR expression. These data indicated that PNE induced depression-like behavior in adolescent female rats via the regulation of neurosteroid levels in the hippocampus.
AICAR (Acadesine/AICA riboside) as an activator of AMPK, can protect renal tubular cells from cisplatin induced apoptosis. But in our experiment, the dorsomorphin (compound C, an inhibitor of AMPK) also significantly reduced cisplatin induced renal tubular cells apoptosis. Accordingly, we tested whether compound C can protect cisplatin-induced nephrotoxicity and the specific mechanism. Here, we treated Boston University mouse proximal tubular cells (BUMPT-306) with cisplatin and/or different dosages of AICAR (Acadesine/AICA riboside) or compound C to confirm the effect of AICAR and compound C in vitro. The AMPK-siRNA treated cells to evaluate whether the protective effect of compound C was through inhibiting AMPK. Male C57BL/6 mice were used to verify the effect of compound C in vivo. Both compound C and AICAR can reduce renal tubular cells apoptosis in dose-dependent manners, and compound C decreased serum creatinine and renal tubular injury induced by cisplatin. Mechanistically, compound C inhibited P53, CHOP and p-IREα during cisplatin treatment. Our results demonstrated that compound C inhibited AMPK, but the renal protective effects of compound C were not through AMPK. Instead, compound C protected cisplatin nephrotoxicity by inhibiting P53 and endoplasmic reticulum (ER) stress. Therefore, compound C may protect against cisplatin-induced nephrotoxicity through pleiotropic effects.
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