Flow regulation of endothelin-1 production in the collecting duct

The collecting duct (CD) is the major site of endothelin-1 (ET-1) synthesis in the body. CD-derived ET-1 is an important autocrine inhibitor of CD Na+ and water reabsorption; deficiency of CD ET-1 causes marked hypertension, Na+ and water retention. Salt and water loading causes an expansion of extracellular fluid volume (ECFV), resulting in increased fluid flow in the CD. ECFV expansion augments CD ET- 1 production, thus suggesting an association between volume loading, natriuresis and diuresis. In cultured cortical collecting duct cells, fluid flow stimulates ET-1 production in a Na+-dependent manner via ENaC and subsequent activation of the mitochondrial Na+/Ca2+ exchanger. In contrast, in mouse inner medullary CD cells, fluid flow regulates ET-1 production in a Na+-independent manner involving Ca2+-dependent signaling via primary cilia/polycystin/purinergic pathways. Finally, a high solute load augments inner medullary CD ET-1 production. Thus, fluid flow regulates ET-1 production differently in the cortical and inner medullary CD; Na+ reabsorption takes place mainly in the cortical CD while water reabsorption occurs in the inner medullary CD. Taken together, the findings in this dissertation provide exciting, novel information about the existence of a complex pathway through which ECFV status controls CD-derived ET-1 production, thereby achieving blood pressure (BP) maintenance and volume homeostasis through acute and sustained regulation of natriuresis and diuresis.