66,67 In support of this, Bickel and colleagues reported that obese Zucker rats with hyperinsulinemia showed increased abundance of NCC and hypertension resulting from Na+ retention.68 Insulin-induced stimulation of NCC activity has been shown to be related to activation of the WNK4-SPAK pathway via the phosphatidylinositol 3-kinase/Akt signaling pathway both in vitro and in vivo in obese Zucker rats and the db/db mouse model of hyperinsulemic metabolic syndrome.69, –71. This evidence concerns the gene SLC12A3 and hypertensive disorder.