The aim of our research is to understand the roles of genes (especially those that regulate blood pressure) on diabetic nephropathy, obesity and preeclampsia in humans using genetically engineered mouse models and computer simulations.

Diabetic nephropathy (DN): DN greatly increases the risk of cardiovascular events. Human endothelial nitric oxide synthase (eNOS) polymorphisms that lead to lower eNOS expression are associated with advanced DN. We found that the absence of eNOS in diabetic mice accelerates DN especially glomerulosclerosis and interstitial fibrosis without increasing oxidative stress. Moreover feeding mice a high fat diet exacerbates this phenotype. eNOS-/- diabetic mouse is one of the most severe animal models of DN. Its mechanisms are under investigation.

Metabolic syndrome: Our mice lacking renin are lean, insulin sensitive, and resistant to diet-induced obesity without changes in food intake and physical activity. They have high metabolic rate, and fatty acid oxidation. They also show gastrointestinal loss of dietary fat. This finding is particularly relevant since renin inhibitors currently in development for the treatment of hypertension may have favorable effects on obesity and insulin sensitivity and its associated metabolic and cardiovascular consequences. We are investigating the role of renin on the metabolic syndrome.

Preeclampsia: sFlt-1 is a soluble form of the receptor for vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). sFlt-1 is highly expressed in placentas of women with preeclampsia. It is a truncated form of Flt-1, secreted into the circulation, and works as a VEGF/PlGF antagonist. Injecting an adenovirus that expresses sFlt-1 into the tail veins of mice caused marked proteinuria and decreased urine volume. Blood pressure of these mice was more than 200 mmHg. Kidney histology shows exactly the same pathologic features as human preeclampsia. We are generating mice that can express sFlt-1 under the control of Cyp1a1 promoter by gene targeting, so that we can induce sFlt-1 expression by giving indole-3-carbinol in their drinking water.