Basolateral Kir4.1 activity in the distal convoluted tubule regulates K secretion by determining NaCl cotransporter activity

Abstract

Purpose of Review Renal potassium (K) secretion plays a key role in maintaining K homeostasis. The classic mechanism of renal K secretion is focused on the connecting tubule (CNT) and cortical collecting duct (CCD) in which K is uptaken by basolateral Na-K-ATPase and it is secreted into lumen by apical ROMK (Kir1.1) and Ca2+ –activated big conductance K channel (BK). Recently, genetic studies and animal models have indicated that inwardly rectifying K channel 4.1 (Kir4.1 or Kcnj10) in distal convoluted tubule (DCT) may play a role in the regulation of K secretion in the aldosterone-sensitive distal nephron (ASDN) by targeting NaCl cotransporter (NCC). This review summarizes recent progresses regarding the role of Kir4.1 in the regulation of NCC and K secretion. Recent Findings Kir4.1 is expressed in the basolateral membrane of the DCT and plays a predominant role in contributing to the basolateral K conductance and in participating in the generation of negative membrane potential. Kir4.1 is also the substrate of src-family tyrosine kinase (SFK) and the stimulation of SFK activates Kir4.1 activity in the DCT. The genetic deletion or functional inhibition of Kir4.1 depolarizes the membrane of the DCT, inhibits ste20-proline-alanine rich kinase (SPAK) and suppresses NCC activity. Moreover, the down-regulation of Kir4.1 increases ENaC expression in the collecting duct and urinary K excretion. Finally, the mice with low Kir4.1 activity in the DCT are hypomagnesemia and hypokalemia. Summary Recent progress in exploring the regulation and the function of Kir4.1 in the DCT strongly indicates that Kir4.1plays an important role in initiating the regulation of renal K secretion by targeting NCC and it may serves as a K sensor in the kidney.

Essential role of Kir5.1 channels in renal salt handling and blood pressure control

“…related subunit, and the resulting K ir 4.1/K ir 5.1 heteromeric channel is clearly distinguishable from the K ir 4.1 homomeric channel (9,15). It was previously thought that K ir 4.1 was the dominant channel driving basolateral K + recycling in the distal tubule, whereas K ir 5.1 was considered to have a modulatory role by increasing conductance and blunting pH sensitivity (10). Indeed, loss-of-function mutations in Kcnj10 cause SeSAME/EAST syndrome associated with hypotension and a severe salt wasting tubulopathy in humans and animal models (20)(21)(22).…”

“…Inwardly rectifying K + channels K ir 4.1 (Kcnj10) and K ir 5.1 (Kcnj16) are highly expressed in the basolateral membrane of distal renal tubules and contribute to Na + reabsorption and K + secretion through the direct control of transepithelial voltage. To define the importance of K ir 5.1 in blood pressure control under conditions of salt-induced hypertension, we generated a Kcnj16 knockout in Dahl salt-sensitive (SS) rats (SS Kcnj16-/-ity and generate the driving force for Cl − and Na + transport (9,10). Recent studies suggest that K ir 4.1 (likely forming heteromeric channels with K ir 5.1) is essential for modulating Na + -Cl -cotransporter (NCC) activity, mediating potassium sensing by distal convoluted tubule (DCT) cells and coupling this signal to apical transport processes (11).…”

Physiology and pathophysiology of potassium homeostasis

“…The unique sensitivity of WNK4 to Cl Ϫ is consistent with this model. There is evidence suggesting that the Kir4.1/5.1 channel in the DCT may act as the sensor by which changes in plasma K ϩ lead to changes in NCC activity (58).…”

Distal tubule basolateral potassium channels

“…This includes a larger single channel conductance and greater pH sensitivity [20,21]. It is important to note that K ir 4.1/K ir 5.1 is the predominant K + basolateral channel and a key determinant of the resting membrane potential in both DCT and CD principal cells [22,23]. This notion is supported by both electrophysiological and pharmacological methods.…”

“…Generally, basolateral K + conductance is higher than the apical one and possibly plays a dominant role in the control of potassium balance [42]. Functionally, K ir 4.1/K ir 5.1 channel recycles K + ions across the basolateral membrane, moved into the cell by the Na + /K + -ATPase, and thus setting a negative basolateral membrane potential to drive Na + reabsorption and control K + secretion in DCT and CCD [3,4]. Using the specific deletion of K ir 4.1 gene in the kidney tubules (part of the thick ascending limb (TAL), DCT, the connecting tubule (CNT) and CCD) Cuevas et al shows that K ir 4.1/K ir 5.1 channel is required to sense and control plasma K + as well as modulate NCC-mediated NaCl transport in DCT [43].…”