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    A System-Wide Approach to Diabetic Nephropathy

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    Type
    Thesis
    Authors
    Palafox, Luis
    Advisors
    Ravasi, Timothy cc
    Committee members
    Gehring, Christoph A cc
    Merzaban, Jasmeen cc
    Program
    Chemical and Biological Engineering
    KAUST Department
    Physical Science and Engineering (PSE) Division
    Date
    2011-07-07
    Permanent link to this record
    http://hdl.handle.net/10754/209378
    
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    Abstract
    Diabetes mellitus is a complex human disease that affects more than 280 million people worldwide. One of the diabetic long-term complications is diabetic nephropathy that it is responsible for 50% of all end-stage renal disease. The complexity of diabetes and the lack of comprehensive systematic studies have halted the development of drugs and clinical therapies for the treatment of diabetes and its major complications. The present project, based on the db/db mice as animal model, investigates the repercussions of diabetes mellitus in the transcriptome as well as the mechanism of action of pirfenidone, an antifibrotic drug, in the treatment of diabetic nephropathy. The study was centered on the system-wide measurements transcriptional state of the mouse kidney. The expression profile of three experimental groups: control, diabetic, and diabetic treated with the drug, were analyzed using expression clustering, gene ontology enrichment analysis, protein-protein interaction network mapping, and gene expression behavior. The results show significant expression dysregulation of genes involved in RNA processing, fatty acid oxidation, and oxidative phosphorylation under the diabetic condition. The drug is able to regulate the expression levels of RNA processing genes but it does not show any effect in the expression profile of genes required in the oxidative phosphorylation and in the fatty acid metabolism. In conclusion diabetes mellitus induce the dysregulation of the splicing apparatus, the oxidative phosphorylation, and the fatty acid metabolic pathway at an expression level. The malfunction of these biological pathways causes cellular stress by increasing the concentration of reactive oxygen species within the cell due to a high oxidative and respiratory activity of mitochondria in addition to the increased demand of the folding machinery as a consequence of a dysregulation of the splicing apparatus. Pirfenidone regulates the expression of RNA processing genes mainly by controlling the expression of peroxisome proliferator-activated receptor-γ coactivator-1α. The expression regulation overcomes the malfunction of the splicing apparatus and reduces the demand of the folding machinery. However the expression of genes annotated for fatty acid oxidation and oxidative phosphorylation do not change after drug treatment.
    Citation
    Palafox, L. (2011). A System-Wide Approach to Diabetic Nephropathy. KAUST Research Repository. https://doi.org/10.25781/KAUST-XTF19
    DOI
    10.25781/KAUST-XTF19
    ae974a485f413a2113503eed53cd6c53
    10.25781/KAUST-XTF19
    Scopus Count
    Collections
    Theses; Physical Science and Engineering (PSE) Division; Chemical Engineering Program

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