A System-Wide Approach to Diabetic Nephropathy

Handle URI:
http://hdl.handle.net/10754/209378
Title:
A System-Wide Approach to Diabetic Nephropathy
Authors:
Palafox, Luis
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.
Advisors:
Ravasi, Timothy ( 0000-0002-9950-465X )
Committee Member:
Gehring, Christoph A ( 0000-0003-4355-4591 ) ; Merzaban, Jasmeen ( 0000-0002-7276-2907 )
KAUST Department:
Physical Sciences and Engineering (PSE) Division
Program:
Chemical and Biological Engineering
Issue Date:
7-Jul-2011
Type:
Thesis
Appears in Collections:
Theses; Physical Sciences and Engineering (PSE) Division; Chemical and Biological Engineering Program

Full metadata record

DC FieldValue Language
dc.contributor.advisorRavasi, Timothyen
dc.contributor.authorPalafox, Luisen
dc.date.accessioned2012-02-04T08:26:12Z-
dc.date.available2012-02-04T08:26:12Z-
dc.date.issued2011-07-07en
dc.identifier.urihttp://hdl.handle.net/10754/209378en
dc.description.abstractDiabetes 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.en
dc.language.isoenen
dc.titleA System-Wide Approach to Diabetic Nephropathyen
dc.typeThesisen
dc.contributor.departmentPhysical Sciences and Engineering (PSE) Divisionen
thesis.degree.grantorKing Abdullah University of Science and Technologyen_GB
dc.contributor.committeememberGehring, Christoph Aen
dc.contributor.committeememberMerzaban, Jasmeenen
thesis.degree.disciplineChemical and Biological Engineeringen
thesis.degree.nameMaster of Scienceen
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