Vasopressin inactivation: Role of insulin-regulated aminopeptidase.

The physiological importance of vasopressin inactivation has long been appreciated, but the mechanisms and potential pathophysiologic roles of this process remain active subjects of research. Human Placental Leucine Aminopeptidase (P-LAP, encoded by the LNPEP gene) is an important determinant of vasopressinase activity during pregnancy and is associated with gestational diabetes insipidus and preeclampsia. Insulin-Regulated Aminopeptidase (IRAP), the rodent homologue of P-LAP, is coregulated with the insulin-responsive glucose transporter, GLUT4, in adipose and muscle cells. Recently, the Tether containing a UBX domain for GLUT4 (TUG) protein was shown to mediate the coordinated regulation of water and glucose homeostasis. TUG sequesters IRAP and GLUT4 intracellularly in the absence of insulin. Insulin and other stimuli cause the proteolytic cleavage of TUG to mobilize these proteins to the cell surface, where IRAP acts to terminate the activity of circulating vasopressin. Intriguingly, genetic variation in LNPEP is associated with the vasopressin response and mortality during sepsis, and increased copeptin, a marker of vasopressin secretion, is associated with cardiovascular and metabolic disease. We propose that in the setting of insulin resistance in muscle, increased cell-surface IRAP and accelerated vasopressin degradation cause a compensatory increase in vasopressin secretion. The increased vasopressin concentrations present at the kidneys then contribute to hypertension in the metabolic syndrome. Further analyses of metabolism and of vasopressin and copeptin may yield novel insights into a unified pathophysiologic mechanism linking insulin resistance and hypertension, and potentially other components of the metabolic syndrome, in humans.