New concepts in endothelin control of sodium balance.

1. Endothelin (ET)-1, which was originally found to be secreted by the vascular endothelium, is highly expressed in the kidney, particularly in the renal medulla. 2. Recent studies using genetic models have provided significant breakthroughs in the role of ET-1 in the kidney. For example, ET-1 in the medullary collecting duct physiologically regulates water and salt reabsorption, thereby controlling blood pressure. Surprisingly, to explain the blood pressure regulation both ET(A) and ET(B) receptors are necessary in collecting duct. In fact, we recently revealed that ET(A) receptor stimulation in the renal medulla was natriuretic and diuretic. 3. The expression and secretion of ET-1 in the renal medulla are regulated by multiple mechanisms, such as changes in osmolality, exaggerated renin-angiotensin system activity and hypoxia. The changes in the renal medullary ET system are likely to work as compensatory 'protective' natriuretic factors in response to high sodium exposure in the kidney. 4. In the present review, we focus on recent publications that describe our current knowledge of the functional role of renal medullary ET-1, including the recently characterized actions of ET(A) receptors, the second messenger systems, mechanisms of stimulating ET-1 production and how the ET system is involved in the development of hypertension.