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.
| Date of Award | Jul 7 2011 |
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| Original language | English (US) |
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| Awarding Institution | - Physical Sciences and Engineering
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| Supervisor | Timothy Ravasi (Supervisor) |
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