Inducible Renal Tubule-specific Insulin Receptor Knockout Mice Have Decreased NCC-mediated Sodium Reabsorption and Reduced Sensitivity to Mineralocorticoid-induced Hypertension in Obesity and Insulin Resistance

Increased renal insulin signaling has been hypothesized to increase sodium reabsorption and drive hypertension observed in humans with obesity and insulin resistance. High fat-fed C57BL/6 mice develop obesity, insulin resistance, increased sodium reabsorption, and a mild sodium-sensitive increase in blood pressure. To investigate the role of tubular insulin signaling in regulating sodium reabsorption we generated an inducible pan-tubular insulin receptor KO mouse (iTIRKO) using a Pax8 promoter-driven tetracycline activator with TetOn-Cre recombinase. Pax8 promoted genes are expressed throughout the tubule, collecting duct, and partially in the liver. Administration of doxycycline in adult iTIRKO mice, but not wild-type (WT) littermates, resulted in a dramatic reduction of insulin receptor immunoreactivity in western blots of whole kidney lysates. When fed a high fat diet, these mice develop obesity identical to WT littermates and C57BL/6 mice. In both low and high fat-fed iTIRKO and WT mice we assayed sod...