ENaC-independent impaired natriuresis and increased blood pressure in mouse models of diet-induced hyperinsulinemia (1086.3)

Patients with obesity develop peripheral insulin resistance, hyperinsulinemia, and hypertension that are associated with cardiovascular disease and death. Hyperinsulinemia increases renal sodium reabsorption, in part through the epithelial sodium channel (ENaC) of the distal nephron, and may increase blood pressure. The molecular determinants of this process are poorly understood, and a mouse model is needed to facilitate discovery. We systematically characterized five potential diet-induced models of the metabolic syndrome in C57BL/6J mice. We measured sodium avidity, ENaC-mediated sodium reabsorption in whole animal and in ex vivo microperfusion experiments as well as blood pressure by radiotelemetry. High-fat (45% or 60% kcal) diet-fed (HFD) mice developed obesity and hyperinsulinemia after 6 weeks while fructose-fed mice lacked hyperinsulinemia. HFD mice demonstrated increased sodium avidity compared to low-fat (10% kcal) fed (LFD) mice as measured by urine sodium excretion after transition to a high ...