Role of SVEP1 in fibrosis, metabolism and blood pressure

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 hypertension.