Caveolin-1 Deficiency Inhibits the Basolateral K+ Channels in the Distal Convoluted Tubule and Impairs Renal K+ and Mg2+ Transport

Abstract

Kir4.1/Kir5.1, in the basolateral membrane of the early DCT (DCT1) in both wild-type (WT) and cav-1-knockout (KO) mice. However, the activity of this basolateral 40-pS K + channel was lower in KO mice than in WT mice. Moreover, the K + reversal potential (an indication of membrane potential) was less negative in the DCT1 of KO mice than in the DCT1 of WT mice. Western blot analysis demonstrated that cav-1 deficiency decreased the expression of the Na + /Cl -cotransporter and Ste20-proline-alanine-rich kinase (SPAK) but increased the expression of epithelial Na + channel-a. Furthermore, the urinary excretion of Mg 2+ and K + was significantly higher in KO mice than in WT mice, and KO mice developed hypomagnesemia, hypocalcemia, and hypokalemia. We conclude that disruption of cav-1 decreases basolateral K + channel activity and depolarizes the cell membrane potential in the DCT1 at least in part by suppressing the stimulatory effect of c-Src on Kcnj10. Furthermore, the decrease in Kcnj10 and Na + /Cl -cotransporter expression induced by cav-1 deficiency may underlie the compromised renal transport of Mg 2+ , Ca 2+ , and K + .

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

“…Thus, a decrease in the basolateral K conductance in the DCT should diminish the driving force for the entry of magnesium ions across the apical membrane thereby inhibiting their absorption in the DCT. This notion is supported by the experiments performed in caveolin-1 knockout mice which have a low basolateral Kir4.1 activity and less negative membrane potential in the DCT in comparison to WT mice [45**]. Consequently, the caveolin-1 knockout mice are associated with increased magnesium excretion and have hypomagnesemia.…”

“…On the other hand, the SFK-induced tyrosine phosphorylation of Kir4.1 stimulates the basolateral K conductance in the DCT [44]. Moreover, caveolin-1 plays a role in mediating the stimulatory effect of SFK on Kir4.1 [45**]. Caveolin-1 is highly expressed in the basolateral membrane of the DCT, CNT and CCD and the disruption of caveolin-1 inhibits the Kir4.1/5.1 activity in the mouse DCT.…”

“…Our recent experiments have demonstrated that Kir4.1 activity in the DCT determines the expression of NCC [20**;45**]. The role of NCC in the regulation of K excretion and K homeostasis has been well recognized by several independent studies [9–11;51**].…”

“…Because Kir4.1 is the only type K channel in the basolateral membrane of the DCT, we hypothesize that Kir4.1 is actually a mediator between NCC and plasma K. This possibility is strongly suggested by the finding that the deletion or the inhibition of Kir4.1 decreases NCC expression [20**;45**]. Fig.…”

Vasopressin-induced stimulation of the Na+-activated K+ channels is responsible for maintaining the basolateral K+ conductance of the thick ascending limb (TAL) in EAST/SeSAME syndrome

“…Moreover, experiments performed in the animal model ( Kcnj10 -/- mice) showed that the NKCC2 expression was not affected by the disruption of Kcnj10 [34]. In contrast, the disruption of Kcnj10 or the down-regulation of Kcnj10 significantly decreased NCC expression and NCC phosphorylation [33,35]. Our previous experiments have further demonstrated that the disruption of Kcnj10 did not alter the basolateral K + conductance and the membrane potential in the TAL[34].…”