Thread by @PAWellingMD

The Aldosterone Paradox, and the Potassium Switch.
A Tweetutorial:

Aldosterone has paradoxical actions: It increases salt reabsorption in states of circulatory volume (CV) depletion without significantly altering potassium balance. Yet, it also increases potassium excretion in states of potassium without altering sodium balance, or CV.

How can one hormone have two contradictory actions, depending on physiological state?

The solution is found in understanding: 1) The factors that regulate potassium excretion, 2) The Potassium Switch.

The kidney regulates urinary potassium excretion to match dietary potassium intake. It does so by varying potassium secretion in the Aldosterone Sensitive Distal Nephron (ASDN). K secretion is maximized by the ASDN when an increase in Aldosterone is accompanied by:

“B” is correct. Among the most important factors that increase potassium secretion are an increase in aldosterone and an increase in sodium delivery to the ASDN. This can be explained by the physiology of potassium secretion in the ASDN.

Potassium secretion is a two-step process. 1. Active transport from blood via the Na/K ATPase, and then 2. Passive efflux into the pro-urine through ROMK and “Big” Potassium (BK) Channels.

Potassium leaves the principal cell preferentially across the apical membrane b/c of a favorable electrical driving force that is established by the Epithelial Sodium Channel, ENaC. Thus, K excretion increases when Na delivery to the ASDN and the activity of ENaC are increased.

Aldosterone activates ENaC whether the hormone goes up with potassium excess or intravascular volume depletion (e.g 28356292). By contrast, sodium delivery to the ASDN is remarkably different in the two different hyperaldosterone states.

In states of CV depletion, distal Na delivery is suppressed as up-stream tubule segments reabsorb more sodium. In potassium excess, distal delivery is enhanced as upstream segments reabsorb less sodium.

In other words:

A new pathway, the “potassium switch” in the Distal convoluted tubule (DCT) offers an explanation for the potassium-dependent effects on sodium delivery. Detailed Reviews: PMID:26654186, 26863326

A quiz:
True or False:
Sodium Chloride reabsorption in the early Distal Convoluted tubule (DCT1) directly activated by aldosterone.

False. Recent studies indicate that aldosterone does not directly activate NaCl transport in the DCT1. PMID:26712527, 26898302, 26762397.

Apparent activation of the thiazide-sensitive sodium-chloride cotransporter (NCC), which mediates nearly all NaCl reabsorption in the DCT, by aldosterone can be explained by the development of hypokalemia and the potassium switch.

NCC is very sensitive to physiological changes plasma potassium (PK) (PMID:26422504), being almost maximally phosphorylated (surrogate for activity) when PK is < or = 2.5 mM and completely shut off when Pk >5.2 mM.
Terker et al from PMID:26422504

These K+-regulated adjustments phosphorylation of NCC (pNCC, a surrogate for activity) have a profound effect on sodium delivery to the ASDN, and thus potassium-secretion. We call this the Potassium-switch pathway:

To become active, NCC must be phosphorylated. This is controlled by a PK-regulated kinase cascade. NCC is phosphorylated by SPAK kinase, which must be phosphorylated by phosphorylated forms of With-no-lysine Kinases, WNK1 and WNK4.

WNK 1 and WNK4 are mutated (gain of function) in Familial Hyperkalemic Hypertension (AKA Gordon’s syndrome, PHAII.)

WNK phosphorylation, in turn, is modulated by changes in PK through effects on membrane potential and the basolateral membrane channel complex, Kir4.1/5.1 (PMID:25565204).

According to current understanding, PK regulates the pathway because WNK phosphorylation is modulated by changes in the intracellular Cl-, which in turn is controlled by membrane voltage (Vm).

Cl- binds to WNK kinase domains (PMID: 24803536), preventing kinase autophosphorylation, and turning the switch pathway off.

Lowering PK hyperpolarizes the membrane, which drives Cl- out of the cell and off the inhibitory binding site, activating the WNKs, and SPAK & NCC, in turn. Switch Pathway on

Increasing plasma potassium, depolarizes the cell, driving Cl- on to WNKs, preventing WNK auto phosphorylation, which ultimately turns off the switch pathway, and turns off sodium reabsorption to increasing sodium delivery to the ASDN.

In states of low CV, Angiotensin II (PMID: 29483225) and Norepi (PMID:30571558) stimulate pNCC through the switch pathway. Both activate Kir4.1/5.1, hyperpolarizing the Vm. By increasing electroneutral sodium chloride reabsorption in the DCT, Na delivery to the ASDN decreases.

This limits potassium secretion in the low CV high aldosterone state!

Emerging studies, presented last November at ASN kidney week, indicate that the PK may also control the switch pathway through regulated dephosphorylation of the cascade. Watch for the papers to come out soon, I hope.

To summarize so far:

Notice: switch activation in the DCT reinforces the effects of aldosterone in the ASDN to reabsorb Na when CV is decreased. But in K excess, the decrease in Na reabsorption in the DCT offsets the increase in the ASDN, so net sodium reabsorption by the kidney remains unchanged.

Also notice, that in potassium secretion is enhanced in potassium excess because sodium delivery to the ASDN is increased, and ENaC is active. But when CV is low, potassium excretion is unchanged because low distal Na delivery offsets the effects of ENaC activation.

Two other effects of potassium on the kidney reinforce the potassium-switch mechanism (see orange columns in summary).
1. Potassium also regulates salt absorption in the proximal tubule, paralleling the effects in the DCT. 28356292

2. Curiously, unlike ENac, a rise in aldosterone is not sufficient to upregulate ROMK or BK (PMID:26654186). These channels are exquisitely regulated, however. Both increase when dietary K increases. It remains to be determined if this occurs via direct effect of K or a hormone.

So, let's put it all together:

So to sum it all up: