K⁺-induced natriuresis is preserved during Na⁺depletion and accompanied by inhibition of the Na⁺-Cl⁻cotransporter

Abstract

During hypovolemia and hyperkalemia, the kidneys defend homeostasis by Na(+) retention and K(+) secretion, respectively. Aldosterone mediates both effects, but it is unclear how the same hormone can evoke such different responses. To address this, we mimicked hypovolemia and hyperkalemia in four groups of rats with a control diet, low-Na(+) diet, high-K(+) diet, or combined diet. The low-Na(+) and combined diets increased plasma and kidney ANG II. The low-Na(+) and high-K(+) diets increased plasma aldosterone to a similar degree (3-fold), whereas the combined diet increased aldosterone to a greater extent (10-fold). Despite similar Na(+) intake and higher aldosterone, the high-K(+) and combined diets caused a greater natriuresis than the control and low-Na(+) diets, respectively (P < 0.001 for both). This K(+)-induced natriuresis was accompanied by a decreased abundance but not phosphorylation of the Na(+)-Cl(-) cotransporter (NCC). In contrast, the epithelial Na(+) channel (ENaC) increased in parallel with aldosterone, showing the highest expression with the combined diet. The high-K(+) and combined diets also increased WNK4 but decreased Nedd4-2 in the kidney. Total and phosphorylated Ste-20-related kinase were also increased but were retained in the cytoplasm of distal convoluted tubule cells. In summary, high dietary K(+) overrides the effects of ANG II and aldosterone on NCC to deliver sufficient Na(+) to ENaC for K(+) secretion. K(+) may inhibit NCC through WNK4 and help activate ENaC through Nedd4-2.

Mechanisms of Renal Control of Potassium Homeostasis in Complete Aldosterone Deficiency

“…NCC mRNA expression was similar in both genotypes, supporting that the aldosterone-dependent regulation of NCC occurs at the posttranscriptional level. 51 Similar to previous data on wild-type rats 37 and mice, 35,36 the high-K + diet also decreased NCC phosphorylation in AS 2/2 mice (Supplemental Figure 9). Although the underlying mechanism for the K + -induced downregulation of NCC is unclear, it likely contributes to the maintenance of K + balance because it augments Na + delivery to the ENaC-expressing ASDN in which then more luminal Na + is available for electrogenic Na + reabsorption in exchange for K + secretion.…”

“…1,34 Decreased NaCl Cotransporter Protein Expression and Activity in AS 2/2 Mice on a 2% K + Diet A K + diet-induced downregulation of the thiazide-sensitive NaCl cotransporter (NCC) in the DCT may participate in the control of urinary K + excretion. 28,[35][36][37] NCC mRNA levels did not differ between AS 2/2 and AS +/+ mice on a 2% K + diet ( Figure 6A). However, the total abundance of NCC and the phosphorylation of NCC at three phospho-sites (pT53, pT58, and pS89) were .50% lower in AS 2/2 mice compared with AS +/+ mice ( Figure 6B).…”

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

“…For example, WNK4 seems to be a negative regulator of NCC under some conditions, but may become a positive regulator in others [72]. The inhibition of NCC by dietary potassium may be mediated by WNK4 [87,110,120], but leaves the question open through which signal DCT cells "sense" dietary potassium. Pathophysiologically, the role of NCC in "essential" hypertension will likely remain a focus of future studies.…”

Cell-specific regulation of L-WNK1 by dietary K+

“…Whereas PCs possess robust basolateral Na ϩ -K ϩ -ATPase activity (3,8,63,71,78), the density of conducting and immunoreactive apical BK channels in these cells is low compared with ICs (17,27,44,59,62,63,68,77,89,100), suggesting that PCs might not be responsible for FIKS. In contrast to PCs, functional and immunoreactive BK channels are abundant in the apical membrane of ICs (17, 27, 44, 59, 62, 63, 68, 77, 100).…”