Virtually all of the
dietary potassium intake is absorbed in the intestine, over 90% of which is excreted by the kidneys regarded as the most important organ of
potassium excretion in the body. The renal excretion of
potassium results primarily from the secretion of
potassium by the principal cells in the
aldosterone-sensitive distal nephron (ASDN), which is coupled to the reabsorption of Na+ by the epithelial Na+ channel (ENaC) located at the apical membrane of principal cells. When Na+ is transferred from the lumen into the cell by ENaC, the negativity in the lumen is relatively increased. K+ efflux, H+ efflux, and Cl- influx are the 3 pathways that respond to Na+ influx, that is, all these 3 pathways are coupled to Na+ influx. In general, Na+ influx is equal to the sum of K+ efflux, H+ efflux, and Cl- influx. Therefore, any alteration in Na+ influx, H+ efflux, or Cl- influx can affect K+ efflux, thereby affecting the renal K+ excretion. Firstly, Na+ influx is affected by the expression level of ENaC, which is mainly regulated by the
aldosterone-
mineralocorticoid receptor (MR) pathway. ENaC gain-of-function mutations (
Liddle syndrome, also known as pseudohyperaldosteronism), MR gain-of-function mutations (Geller syndrome), increased
aldosterone levels (primary/secondary
hyperaldosteronism), and increased
cortisol (
Cushing syndrome) or
deoxycorticosterone (
hypercortisolism) which also activate MR, can lead to up-regulation of ENaC expression, and increased Na+ reabsorption, K+ excretion, as well as H+ excretion, clinically manifested as
hypertension,
hypokalemia and
alkalosis. Conversely, ENaC inactivating mutations (
pseudohypoaldosteronism type 1b), MR inactivating mutations (
pseudohypoaldosteronism type 1a), or decreased
aldosterone levels (
hypoaldosteronism) can cause decreased reabsorption of Na+ and decreased excretion of both K+ and H+, clinically manifested as
hypotension,
hyperkalemia, and
acidosis. The ENaC inhibitors
amiloride and
Triamterene can cause manifestations resembling
pseudohypoaldosteronism type 1b; MR antagonist
spironolactone causes manifestations similar to
pseudohypoaldosteronism type 1a. Secondly, Na+ influx is regulated by the distal delivery of water and
sodium. Therefore, when loss-of-function mutations in Na+-K+-2Cl- cotransporter (NKCC) expressed in the thick ascending limb of the loop and in
Na+-Cl- cotransporter (NCC) expressed in the distal convoluted tubule (
Bartter syndrome and
Gitelman syndrome, respectively) occur, the distal delivery of water and
sodium increases, followed by an increase in the reabsorption of Na+ by ENaC at the collecting duct, as well as increased excretion of K+ and H+, clinically manifested as
hypokalemia and
alkalosis.
Loop diuretics acting as NKCC inhibitors and
thiazide diuretics acting as NCC inhibitors can cause manifestations resembling
Bartter syndrome and
Gitelman syndrome, respectively. Conversely, when the distal delivery of water and
sodium is reduced (e.g.,
Gordon syndrome, also known as
pseudohypoaldosteronism type 2), it is manifested as
hypertension,
hyperkalemia, and
acidosis. Finally, when the distal delivery of non-
chloride anions increases (e.g.,
proximal renal tubular acidosis and congenital
chloride-losing
diarrhea), the influx of Cl- in the collecting duct decreases; or when the excretion of
hydrogen ions by collecting duct intercalated cells is impaired (e.g.,
distal renal tubular acidosis), the efflux of H+ decreases. Both above conditions can lead to increased K+ secretion and
hypokalemia. In this review, we focus on the regulatory mechanisms of renal
potassium excretion and the corresponding diseases arising from dysregulation.