Recent advances in distal tubular potassium handling

Abstract

It is well known that sodium reabsorption and aldosterone play important roles in potassium secretion by the aldosterone-sensitive distal nephron. Sodium- and aldosterone-independent mechanisms also exist. This review focuses on some recent studies that provide novel insights into the sodium- and aldosterone-independent potassium secretion by the aldosterone-sensitive distal nephron. In addition, we discuss a study reporting on the regulation of the mammalian potassium kidney channel ROMK by intracellular and extracellular magnesium, which may be important in the pathogenesis of persistent hypokalemia in patients with concomitant potassium and magnesium deficiency. We also discuss outstanding questions and propose working models for future investigation.

Fig. 1.

Model of intercalated cell potassium secretion. Due to a large basolateral chloride conductance (not shown), the basolateral membrane potential (V_bl) of the intercalated cell is close to the equilibrium potential for chloride, approximately −36 mV. Due to electrogenic sodium reabsorption through the epithelial sodium channel (ENaC) in neighboring principal cells (not shown), a transepithelial potential (V_TE) is generated. If this is about the same as V_bl, the apical membrane potential (V_a) of the intercalated cell will be ∼0 mV (see Ref. for a more detailed discussion). This relatively depolarized V_a results in a higher open probability for the voltage-gated potassium channels BK and Kv1.3 and provides a strong electric driving force for potassium secretion. By coupling potassium secretion to chloride secretion, a sodium-independent component of potassium secretion can be achieved. An apical chloride channel has yet to be identified, but an attractive hypothesis is that a member of the voltage- and calcium-dependent TMEM16 family could provide this function. On the basolateral side, potassium uptake may occur through the Na-K-ATPase, but because this is present at only low levels in intercalated cells, additional uptake may occur through Na⁺-K⁺-2Cl⁻ cotransporter isoform 1 (NKCC1). If Na-K-ATPase is limiting, the cotransported sodium could be recycled either through the ouabain-insensitive Na-ATPase, or through other unidentified mechanisms, such as a Na-HCO₃⁻ cotransporter (not shown).

Fig. 2.

Integrated regulation of potassium secretion by WNK1. A high-potassium diet decreases the ratio of full-length L-WNK1 to the kidney-specific transcript KS-WNK1, which lacks the kinase domain and inhibits L-WNK1 in a dominant-negative fashion. This occurs by upregulation of KS-WNK1 and downregulation of L-WNK1 by a high potassium diet. As a result, NKCC2 and Na⁺-Cl⁻ cotransporter (NCC) levels and activity are downregulated. This results in decreased sodium reabsorption in the thick ascending limb of the loop of Henle and the distal convoluted tubule, nephron segments in which electroneutral sodium and chloride reabsorption occurs. Increased sodium is therefore delivered to the downstream aldosterone-sensitive distal nephron, providing additional sodium for electrogenic reabsorption. This allows a more negative transepithelial voltage to develop and increases the driving force for potassium secretion. The decrease in the ratio of L- over KS-WNK1 may increase the level of ROMK, allowing greater potassium secretion across the apical membrane of principal cells in the aldosterone-sensitive distal nephron (connecting tubule, collecting duct). Flow-dependent potassium secretion, for example by BK, is also stimulated by the increased distal flow. The role of WNK1 in BK, Kv1.3 channels and potassium secretion through intercalated cells remains unexplored.