Last update:
08-Sep-2020

Arterial hypertension is one of the most devastating diseases in modern societies. As early as 1920, Frederick Allen showed that sodium restriction ameliorates hypertension. After that, in 1929, Robert Berghoff and Angelo Geraci showed in an observational study that administration of high sodium chloride increases blood pressure where as substitution of sodium chloride by an equimolar quantity of sodium bicarbonate has no effect on blood pressure. It was the first clinical study in humans showing that chloride anions may be responsible for the high blood pressure observed with increased salt consumption. During the '70s, it was experimentally proven that chloride anions play a crucial role in intracellular volume regulation and in signalling renin secretion via macula densa cells. In the mid '90s, the discovery of sodium chloride transporter mutations as candidates for Bartter and Gitelman syndromes pointed toward the possibility that chloride anions may play a crucial role in blood pressure regulation. In the beginning of second millennium, the discovery of a new class of protein kinases, named with-no-lysine kinases (WNKs), and shortly thereafter the discovery that two mutations in WNK1 and WNK4 are candidates for an inherited form of familial hypertension with hyperkalemia and acidosis known as pseudohypoaldosteronism type II or Gordon's syndrome raised the question of the possible pathogenic role of sodium-chloride co-transporters in the distal nephron in hypertension. Subsequent research supports that WNKs act as intracellular chloride sensors and regulate the activity of transepithelial sodium-chloride cotransporters in the distal nephron. Moreover, it was experimentally shown that the sodium-independent chloride-bicarbonate exchanger pendrin in the collecting tubule plays a crucial role in transepithelial sodium chloride transport in this nephron segment. In conclusion, after nearly a century of intense research, it has been shown that sodium transcellular transport in distal nephron epithelia is accomplished mainly via chloride co-transport. Furthermore, chloride anions play a crucial role in renin secretion and in cell volume regulation. WNKs are the housekeepers of intracellular chloride concentration. We suggest that it may be time to talk of "chloride-sensitive" and not of "sodium sensitive" hypertension.

Key words: Chloride anion, Pendrin, Sodium sensitive hypertension, With no-lysine-kinases.