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dc.contributor.advisorTurner, Neil
dc.contributor.advisorBellamy, Christopher
dc.contributor.authorZhou, Yu Simona
dc.date.accessioned2012-05-18T13:30:47Z
dc.date.available2012-05-18T13:30:47Z
dc.date.issued2011-11-25
dc.identifier.urihttp://hdl.handle.net/1842/5959
dc.description.abstractIntroduction Podocytes are terminally differentiated, highly specialized glomerular cells that form the final barrier to protein loss. Podocyte injury is characterised by proteinuria. Proteinuria is an important prognostic marker in kidney diseases, and lowering proteinuria has become a principal clinical goal. Compelling evidence supports the notion that continuing loss of podocytes plays a major role in the initiation and progression of glomerular diseases. It is my hypothesis that interventions that reduce the disruption by rescuing susceptible podocytes next to injured ones are potential therapies to restore podocyte phenotype and filtration behaviour, thereby protecting the kidney from progressive deterioration. Prevention of this damage, or ways to aid its recovery, could therefore be important to improving the management of human kidney diseases. Methods Transgenic mice expressing the human diphtheria toxin receptor on podocytes had been previously generated in our laboratory. Characterization of two lines showed that graded specific podocyte injury could be induced by single intraperitoneal injection of diphtheria toxin. Eight-week intervention studies involved administration of oral drug in water or food from 24h after toxin injection. Two control groups received no drug or were non-transgenic (wild-type) littermates. Primary endpoints were glomerulosclerosis and kidney function (serum creatinine). Other readouts included blood pressure, albuminuria, serum albumin, podocyte quantification and collagen staining of kidney. The angiotensin converting enzyme inhibitor (ACEi) captopril was tested because of its proven protective effect on renal function in patients with proteinuria. Subsequently another proteinuria-reducing drug, the endothelin receptor A antagonist sitaxsentan was tested alone and in combination with captopril. Results Captopril reduced proteinuria and ameliorated scarring, with matrix accumulation and glomerulosclerosis falling almost to baseline. Podocyte counts were reduced after toxin administration and showed no significant recovery irrespective of captopril treatment. In the following sitaxsentan and captopril combined intervention study, glomerular scarring was significantly reduced in all drug-treated groups either alone or in combination, but only combination drug treatment reduced glomerular damage to levels comparable to wild-type controls, demonstrating a synergistic effect of the two agents. Similarly, serum creatinine was lowered further in combined but not single drug-treated groups. Blood pressure of all drug treated mice was lowered compared to the placebo group. Surprisingly in this second study there were no significant differences in proteinuria between treated and untreated groups. Conclusion These results support the hypothesis that continuing podocyte dysfunction is a key abnormality in proteinuric disease, and plays a major role in progressive glomerulosclerosis. Both captopril and sitaxsentan alone or in combination provided protection without substantial preservation or restoration of podocyte numbers at the degree of injury induced in these experiments. Combined therapy showed a synergistic effect in protecting the kidney from progressive damage. These results suggest that protection may be at least partly due to change in podocyte phenotype. The model is ideal for studying strategies to protect the kidney from progressive damage following specific podocyte injury. Further elucidations on the mechanism of action of the drugs may aid development of superior future therapeutic treatments in the field of renal diseases.en
dc.contributor.sponsorMedical Research Council (MRC)en
dc.contributor.sponsorKidney Research UKen
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.subjectPodocyteen
dc.subjectkidney diseaseen
dc.subjectglomerulosclerosisen
dc.subjectFSGSen
dc.titlePodocyte repair and recovery in kidney diseaseen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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