|dc.contributor.author||Sime, Nicole Elizabeth Lennon||
|dc.description.abstract||Sushi, von Willebrand factor type A, epidermal growth factor and pentraxin domain
containing 1 (SVEP1) is an extracellular matrix protein which may bind to cell surface
molecules such as integrins. A non-synonymous single amino acid polymorphism in
the Svep1 gene is associated with a 14% increased risk of coronary heart disease, a
13% higher risk of type 2 diabetes and a 1mmHg increase in systolic blood pressure.
Expression of the SVEP1 gene is increased in the kidney in the Cyp1a1mRen2 rat
model of diabetes and hypertension previously developed in our lab. SVEP1 is also
known to be upregulated in human diabetic nephropathy and is upregulated in rodent
models of renal fibrosis. I hypothesized that Svep1 played a role in renal fibrosis,
diabetes and blood pressure. Hence, the primary goal of this thesis was to investigate
the role of SVEP1 and in the pathogenesis of diabetes, hypertension and renal fibrosis.
Svep1 gene expression is increased in the kidney in the DOCA-salt-angII-uninephrectomy
model of hypertension and following UUO. SVEP1 hemizygous mice
showed no differences in expression of pro-fibrotic genes after UUO compared to
wildtype littermates. No overt metabolic phenotype was exhibited by the Svep1
hemizygous mice, however there was a significant decrease in fat depot weights after
high fat diet (HFD) and a significant increase in blood glucose concentrations during
the glucose tolerance test at the 12 week time point in hemizygous Svep1 mice
compared with wild-type controls. After telemetry analysis of blood pressure no
difference was seen in blood pressure but SVEP1+/-animals had an increased heart rate
of 100 beats per minute compared to wildtype animals.
Svep1 expression is increased in the kidney in models of hypertension and fibrosis,
however loss of one Svep1 allele did not alter the severity of fibrosis in the UUO model
or significantly alter glucose tolerance after high fat diet. However, the high fat diet
experiment was a pilot study and should be repeated with a larger number of animals.
In addition, generation of a mouse with the human point mutation could determine the
mechanisms by which this extracellular matrix protein confers risk of diabetes and
|dc.publisher||The University of Edinburgh||en
|dc.subject||high blood pressure.||en
|dc.title||Role of SVEP1 in fibrosis, metabolism and blood pressure||en
|dc.type||Thesis or Dissertation||en
|dc.type.qualificationname||PhD Doctor of Philosophy||en