Chloride: Queen of the Electrolytes

In June's edition of JASN Jacques et al. highlighted the emerging importance of the role of chloride in the pathogenesis of hypertension. Their group developed a mouse model that over expressed the protein pendrin in the aldosterone-sensitive region of the distal tubule. These mice developed hypertension that was attributed to increased NaCl absorption driven by over expression and increased activity of the pendrin chloride exchanger.

Pendrin was first described as a chloride channel in the kidney in the early 2000s. Pendrin is a chloride-bicarbonate exchange protein that facilitates the electroneutral movement of chloride to the intracellular space and bicarbonate to the extracellular space or urinary space. This channel is also found in the thyroid and inner ear and is the gene that causes Pendreds syndrom.

It is now widely accepted that the pressor effects of salt (NaCl) are dependent on Na as the major determinant of intravascular volume and thus hypertension. It has also been demonstrated that for Na to mediate a hypertensive effect, it needs to be in the form of NaCl (Berghoff and Geraci, Intern Med J 56:395-397). In their study, Berghoff and Geraci showed that subjects on a high NaCl diet but not on a high NaBicarbonate diet developed hypertension. These experiments have been reproduced in human and animal models. Interestingly, hypertensive and normotensive subjects switched from a NaCl diet to an equimolar NaBicarbonate diet experienced a decrease in blood pressure.

Pendrin is normally found in the type B Intercalated cells of the aldosterone region of the nephron. Recently published studies by the same group suggest that pendrin can also work in tandem with the Na-dependent chloride/bicarbonate exchanger (this is a different channel to pendrin and is also found in the CCD) resulting in electroneutral NaCl absorption and that this process is thiazide sensitive.

In JASNs June edition, the Jacques group showed that pendrin mediates chloride absorption distally and that this is the driving force for Na absorption distally either through the ENaC and/or Ndcbe channels. The significance of their findings are that 1) chloride is required for NaCl absorption in ‘salt sensitive’ hypertension and that 2) pendrin is the channel that facilitates the absorption of chloride.

On the basis of this paper and other papers showing similar findings with regard to Pendrin's role in NaCl balance the authors suggest their work solidifies the concept of chloride-sensitive hypertension.

It must be remembered that these studies don’t dispute that Na is primary in maintaining blood volume and driving hypertension. However, chloride absorption is a necessary requirement for the absorption of Na in the setting of a salt load causing hypertension. Thus, Chloride might be the queen and Na the king of extracellular solutes!

See these previous posts on Pendrin function in the kidney.

Posted by Andrew Malone

Tell me who your friends are and I will tell you who you are: NaHCO3 isn't NaCl

When managing patients with metabolic acidosis, some nephrologists are afraid of prescribing NaHCO3 because of the potential adverse consequences of increasing ECF volume and worsening blood pressure. However, there is significant evidence that the kidneys handle NaCl in a different way than they handle NaHCO3.


As far back as 1929, there have been several reports showing that blood pressure increased in hypertensive individuals on a high NaCl diet, but not on high NaHCO3 diet (Berghoff RS et al. IMJ. 1929; 56: 395–397). In 1983, Kurtz et al published a seminal paper in Science. They performed studies in uninephrectomized rats treated with desoxycorticosterone (DOC), a model for sodium-dependent hypertension. They exposed these animals to a high NaCl diet, a high NaHCO3, or Na+-ascorbate diet. The rats exposed to a high NaCl diet developed more hypertension that rats exposed to non-chloride Na+ salts. This study strongly suggests that Na+ has to be administered as a Cl- salt to raise blood pressure.

The explanation for this might be found in the cross talk between Pendrin and the epithelial sodium channel (ENaC) . Pendrin is a Cl-/HCO3- exchanger located in the apical membrane of type B and non-A-non-B intercalated cells. ENaC is a major sodium transporter located in the apical membrane of principal cells. Pendrin and ENaC reside in two different cell types that do not communicate through gap junctions. Therefore, it is not readily apparent that Na+ reabsorption is linked molecularly to Cl- transport. Despite this, significant evidence indicates that Pendrin plays a major role in ECF volume regulation , possibly via its influence on ENaC. How does this occur? The mechanism has not been completely elucidated but because Pendrin mediates HCO3- secretion, an increase in luminal or basolateral HCO3- is at least partially responsible for ENaC activation and subsequent sodium retention.