The associations between insulin resistance, hyperinsulinaemia, and hypertension are well recognized. Hyperinsulinaemia induces hypertension through increased renal tubular reabsorption of sodium and water, increased sympathetic nervous system activity, proliferation of vascular smooth muscle cells, and alterations of transmembrane cation transport. At physiological concentrations, insulin decreases urinary sodium excretion, an action mediated by binding to specific high-affinity receptors. Insulin resistance is present also in strains of rats with genetic hypertension (spontaneously hypertensive and Dahl salt-sensitive rats) that can be utilized as models to study the molecular mechanisms of this abnormality. In normal rats, the number and mRNA levels of insulin receptors in the kidney are inversely related with dietary sodium content, suggesting the existence of a feedback mechanism that limits insulin-induced sodium retention when extracellular fluid volume is expanded. We have investigated the relationships between dietary sodium intake and renal insulin receptors in spontaneously hypertensive rats and have found that in this strain the feedback mechanism is abolished. In addition, spontaneously hypertensive rats have decreased expression of the insulin receptor gene in the liver and decreased receptor autophosphorylation and phosphorylation of an endogenous substrate (IRS-1) in liver and muscle. These observations provide a potential explanation for the decreased sensitivity to insulin present in spontaneously hypertensive rats. In these rats, the loss of the capability to down-regulate insulin receptor in the kidney when extracellular fluid volume is expanded can lead to further sodium retention and might play a role in the development and maintenance of hypertension.
