Role of endothelin in thick ascending limb sodium chloride transport.
The thick ascending limb of the loop of Henle reabsorbs 20-30% of filtered sodium chloride (NaCl) and generates the osmotic gradient necessary for water absorption in the distal nephron. It is second only to the collecting duct as a source of renal endothelin (ET)-1, which inhibits NaCl reabsorption in the thick ascending limb by reducing NaCl entry into the cell via the furosemide-sensitive Na(+)/K(+)/2 Cl(-) cotransporter. The mechanism by which this occurs appears to be due to activation of ET(B) receptors, phosphatidylinositol 3 kinase and Akt, and enhanced nitric oxide production by nitric oxide synthase 3. ET-1 may inhibit thick ascending limb NaCl absorption in either an autocrine or paracrine fashion. High-salt intake elevates ET-1 release by thick ascending limbs, although the molecular mechanism involved is unknown. Enhanced ET-1 release and inhibition of thick ascending limb NaCl absorption are thought to be among the mechanisms required to eliminate a salt load without increasing blood pressure. However, we still have much to learn about how ET-1 inhibits thick ascending limb NaCl absorption, how release and processing of ET-1 are regulated, and the receptors involved.