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Transcriptome results in hippocampus and cortex of KCNMA1-/- (BK KO) mice.

ABSTRACT: In this study, we used RNA-Seq to analyze the transcriptome of BK KO/WT mice hippocampus and cortex, and performed transcriptome profiling to characterize the differentially expressed genes. A total of 652 genes were screened with the threshold of significance at P < 0.05 and |log2foldchange| > 0.58, among which 382 genes were down-regulated and 270 genes were up-regulated in hippocampus tissues. In cortex tissues, we detected a total of 561 differentially expressed genes with the threshold of significance at P < 0.05 and |log2foldchange| > 0.58, including 162 up-regulated genes and 399 down-regulated genes. In order to better understand the potential functions of differentially expressed genes, Gene Ontology (GO) enrichment analysis was carried out to assess the involved pathways. Biological process pathway in GO analysis results showed that development process and biological adhesion were enriched. The results of kyoto encyclopedia of genes and genomes (KEGG) showed that insulin secretion, axon guidance, p53 signaling pathway, HIF-1 signaling pathway and calcium signaling pathway were enriched in hippocampus. On the other hand, cortical KEGG results showed that cell adhesion molecules (CAMs), ECM-receptor interaction, phagosome and calcium signaling pathway were enriched. Dysregulation of gene expression, especially astrocyte activation, neuroinflammation and autophagy, might be the molecular mechanism of BK-LOF meditated epilepsy. This study explores the possible mechanism of epilepsy by transcriptome, reveals the relationship between KCNMA1-LOF and epilepsy, and provides a possible molecular template for individualized treatment of epilepsy.

ORGANISM(S): Mus musculus

PROVIDER: GSE191038 | GEO | 2021/12/18

REPOSITORIES: GEO

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Project description:<h4><strong>INTRODUCTION: </strong>Approximately 1% of the world's population is impacted by epilepsy, a chronic neurological disorder characterized by seizures. One-third of epileptic patients are resistant to AEDs, or have medically refractory epilepsy (MRE). One non-invasive treatment that exists for MRE includes the ketogenic diet, a high-fat, low-carbohydrate diet. Despite the KD's success in seizure attenuation, it has a few risks and its mechanisms remain poorly understood. The KD has been shown to improve metabolism and mitochondrial function in epileptic phenotypes. Potassium channels have implications in epileptic conditions as they have dual roles as metabolic sensors and control neuronal excitation.</h4><h4><strong>OBJECTIVES: </strong>The goal of this study was to explore changes in the lipidome in hippocampal and cortical tissue from Kv1.1-KO model of epilepsy.</h4><h4><strong>METHODS: </strong>FT-ICR/MS analysis was utilized to examine nonpolar metabolome of cortical and hippocampal tissue isolated from a Kv1.1 channel knockout mouse model of epilepsy (n = 5) and wild-type mice (n = 5).</h4><h4><strong>RESULTS: </strong>Distinct metabolic profiles were observed, significant (p < 0.05) features in hippocampus often being upregulated (FC ≥ 2) and the cortex being downregulated (FC ≤ 0.5). Pathway enrichment analysis shows lipid biosynthesis was affected. Partition ratio analysis revealed that the ratio of most metabolites tended to be increased in Kv1.1-/-. Metabolites in hippocampal tissue were commonly upregulated, suggesting seizure initiation in the hippocampus. Aberrant mitochondrial function is implicated by the upregulation of cardiolipin, a common component in the mitochondrial membrane.</h4><h4><strong>CONCLUSION: </strong>Generally, our study finds that the lipidome is changed in the hippocampus and cortex in response to Kv1.1-KO indicating changes in membrane structural integrity and synaptic transmission.</h4>

Project description:Diabetic kidney disease is the major cause of end-stage kidney failure worldwide. Podocyte damage is one of the hallmarks of diabetic nephropathy, where the loss of the podocyte filtration barrier leads to proteinuria and progressive renal damage. Bradykinin (BK) is a vasoactive peptide that was shown to play an important role in the progression of renal damage. In this study, we aim to evaluate the changes in protein expression profiles of rat podocytes upon the treatment with BK by an advanced proteomics platform in conjunction with bioinformatics and pathway enrichment analysis. This analysis will help in discovering core effectors whose upstream and downstream protein profile can elucidate signaling mechanisms underlying BK’s modulation of the podocyte biology. Cultured immortalized rat podocytes were treated with BK at 10-7 M for 3 and 6 hours. Proteome profile was evaluated by LC-MS/MS analysis, and pathway enrichment analysis was performed on the resulting differential proteomic data. Proteomic analysis of podocytes treated by BK revealed 61 proteins that were differentially altered (up or downregulated) in response to BK treatment compared to unstimulated control podocytes. Pathway enrichment analysis suggested an inhibition of the cell death pathway and the involvement of elements of the cytoskeletal activity as well as activation of the inflammatory pathways. Of interest, one of the inflammatory proteins that were identified to be induced by BK treatment is Prostaglandin H Synthase-2 (PTGS-2, also known as COX-2). The upregulation of COX-2 by BK treatment was validated by western blot analysis. In addition, treatment of podocytes with BK significantly induced the production and release of PGE2 and this effect was inhibited by both COX-2 and MAPK inhibitors, demonstrating that the production of PGE2 by BK is mediated via a COX-2 and MAPK-dependent mechanisms. The findings of the present study provide a global understanding of the effector modulated proteome in response to BK treatment, and also reveal BK as an important modulator in the arachidonic acid metabolism pathway and a potential player in the progression of diabetic nephropathy.

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Transcriptome results in hippocampus and cortex of KCNMA1-/- (BK KO) mice.

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