Plasma Potassium Determines NCC Abundance in Adult Kidney-Specific γENaC Knockout

Abstract

The amiloride-sensitive epithelial sodium channel (ENaC) and the thiazide-sensitive sodium chloride cotransporter (NCC) are key regulators of sodium and potassium and colocalize in the late distal convoluted tubule of the kidney. Loss of the ENaC subunit leads to a perinatal lethal phenotype characterized by sodium loss and hyperkalemia resembling the human syndrome pseudohypoaldosteronism type 1 (PHA-I). In adulthood, inducible nephron-specific deletion ofENaC in mice mimics the lethal phenotype observed in neonates, and as in humans, this phenotype is prevented by a high sodium (HNa)/low potassium (LK) rescue diet. Rescue reflects activation of NCC, which is suppressed at baseline by elevated plasma potassium concentration. In this study, we investigated the role of the ENaC subunit in the PHA-I phenotype. Nephron-specificENaC knockout mice also presented with salt-wasting syndrome and severe hyperkalemia. Unlike mice lacking ENaC orΕΝaC, an HNa/LK diet did not normalize plasma potassium (K) concentration or increase NCC activation. However, when K was eliminated from the diet at the time that ENaC was deleted, plasma K concentration and NCC activity remained normal, and progressive weight loss was prevented. Loss of the late distal convoluted tubule, as well as overall reduced ENaC subunit expression, may be responsible for the more severe hyperkalemia. We conclude that plasma K concentration becomes the determining and limiting factor in regulating NCC activity, regardless of Na balance in ENaC-deficient mice.

Interaction between Epithelial Sodium Channel γ-Subunit and Claudin-8 Modulates Paracellular Sodium Permeability in Renal Collecting Duct

“…The Nephron-Specific KO of g-ENaC Is Associated with a Decrease in Claudin-8 Abundance in Mouse Kidney To investigate potential physiologic interactions between transcellular and paracellular pathways in vivo, we assessed claudin-4 and claudin-8 protein abundance in Dox-induced, kidney tubule-specific, g-ENaC KO mice. 18 As expected, in kidney cortex, Western blot analyses revealed the absence of g-ENaC protein in 4-week-old g-ENaC KO mice as compared with control wild-type littermates ( Figure 7, A and B); this was accompanied by a significant decrease in claudin-8 abundance that is specifically expressed along the collecting system (connecting tubule and CD). 9 This decrease in claudin-8 protein expression was specific because abundance of claudin-4, which is mostly expressed along the collecting system, remained unchanged.…”

“…Animal maintenance and protocols were done as described. [16][17][18] Animal experiments were performed according to the guidelines of the local ethical committee and after authorization of the cantonal authorities.…”

The serine‐threonine kinase PIM3 is an aldosterone‐regulated protein in the distal nephron

“…In order to gain a primary hint that PIM3 may be involved in aldosterone‐dependent regulation of electrolytes, blood volume, or blood pressure, we studied in wild‐type and Pim3 KO mice aldosterone, plasma renin activity and mRNA expression in the kidney. Indeed, similarly to Sgk1 KO (Wulff et al ; Fejes‐Toth et al ; Faresse et al ), Scnn1a,b,c KO (Perrier et al ; Boscardin et al , ) and Nr3c2 KO (Canonica et al ; Terker et al ), but not Tsc22d3 (GILZ) KO mice (Rashmi et al ), these animals displayed higher aldosterone levels, accompanied by elevated PRA and renin mRNA expression in the kidney.…”

Glucocorticoid receptor activation stimulates the sodium-chloride cotransporter and influences the diurnal rhythm of its phosphorylation

“…We did not measure plasma potassium in mice treated with spironolactone, but MR antagonism is widely recognized as inducing hyperkalemia, which in turn dephosphorylates NCC (37,47). Mice with kidney-specific deletion of the ␥-epithelial sodium channel subunit are severely hyperkalemic and show reduced NCC expression (5). Prevention of hyperkalemia through dietary potassium restriction and/or treatment with a potassium binder restored NCC abundance to control levels, suggesting that plasma potassium is a primary regulator of the NCC pool.…”