Activation of the kidney sodium chloride cotransporter by the β2-adrenergic receptor agonist salbutamol increases blood pressure

Poulsen, Søren Brandt; Liu, Cheng; Pentón, David; Kortenoeven, Marleen L. A.; Matchkov, Vladimir; Loffing, Johannes; Little, R. A.; Murali, Sathish Kumar; Fenton, Robert A.

doi:10.1016/j.kint.2021.04.021

Cited by 18 publications

(17 citation statements)

References 67 publications

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“…On the other hand, Terker et al showed that acute adrenergic stimulation increased the abundance of pNCC via BAR1 stimulation in mice (Terker et al, 2014). More recently, it has been shown that pharmacological stimulation of BAR2 with salbutamol increases both NCC phosphorylation and systolic blood pressure, the latter effect blunted by thiazide (Poulsen et al, 2021). In the present study, we demonstrated that also BAR3 plays an additional, crucial role in NCC modulation.…”

Section: Discussionsupporting

confidence: 65%

“…Our hypothesis is indeed that the reduction of WNK-SPAK signaling in the kidney upon BAR3 ko induces the reduction of NCC phosphorylation and activity in these mice. Although BAR2 is also involved in the activation of SPAK and WNK (Poulsen et al, 2021), in the kidney of BAR1/2 ko mice, the activity of SPAK and WNK resulted almost normal or slightly upregulated compared to their controls, thus suggesting that BAR3 alone is sufficient to preserve the WNK-SPAK pathway activation in the kidney under sympathetic stimulation.…”

Section: Discussionmentioning

confidence: 95%

“…Here, we focused on the possible functional role of BAR3 in DCT where it localized at the basolateral membrane of epithelial cells expressing the thiazide-sensitive sodium-chloride cotransporter (NCC) at the apical side (Procino et al, 2016;Poulsen et al, 2021). NCC tightly tunes renal sodium reabsorption in DCT to fit blood pressure changes.…”

Section: Introductionmentioning

confidence: 99%

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Activation of the Thiazide-Sensitive Sodium-Chloride Cotransporter by Beta3-Adrenoreceptor in the Distal Convoluted Tubule

et al. 2021

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We previously showed that the beta-3 adrenergic receptor (BAR3) is expressed in most segments of the nephron where its agonism promotes a potent antidiuretic effect. We localized BAR3 in distal convoluted tubule (DCT) cells expressing the thiazide-sensitive sodium-chloride cotransporter (NCC). Aim of this study is to investigate the possible functional role of BAR3 on NCC modulation in DCT cells. Here, we found that, in mice, the knockout of BAR3 was paralleled by a significant attenuation of NCC phosphorylation, paralleled by reduced expression and activation of STE-20/SPS1-related proline-alanine-rich kinase (SPAK) and WNKs the main kinases involved in NCC activation. Conversely, in BAR1/2 knockout mice, we found reduced NCC abundance with no changes in the phosphorylation state of NCC. Moreover, selective BAR3 agonism promotes both SPAK and NCC activation in wild-type mouse kidney slices. In conclusion, our findings suggest a novel role for BAR3 in the regulation of NCC in DCT.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Activation of the Thiazide-Sensitive Sodium-Chloride Cotransporter by Beta3-Adrenoreceptor in the Distal Convoluted Tubule

et al. 2021

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“…Tubules were then allowed to sediment whereafter media was removed and replaced by 3 ml media with the desired aldosterone and K + concentrations. Tubules were then incubated at 37°C and 5% CO 2 for 21 h. Preincubation of tubules for 21 h and subsequent exposure to 10 µM salbutamol for 2 h (Selleckchem, Houston, TX) increased pT58-NCC [ Supplementary Figure S4 ( Poulsen et al, 2021 ),], thus documenting the viability of the tubules.…”

Section: Methodsmentioning

confidence: 99%

Dissecting the Effects of Aldosterone and Hypokalemia on the Epithelial Na+ Channel and the NaCl Cotransporter

2022

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Primary hyperaldosteronism (PA) is characterized by aldosterone excess and hypertension. This may be linked to increased renal Na+ reabsorption via the epithelial Na+ channel (ENaC) and the NaCl cotransporter (NCC). The majority of PA patients have normal plasma K+ levels, but a subset of cases are associated with hypokalemia. High NCC levels observed in long-term studies with aldosterone-infused rodents have been attributed to direct effects of aldosterone. Aldosterone can also increase active phosphorylated NCC (pT58-NCC) acutely. However, direct effects of aldosterone on NCC have been contested by recent studies indicating that it is rather an indirect effect of hypokalemia. We therefore set out to determine isolated long-term aldosterone and K+ effects on ENaC and NCC using various in vivo and ex vivo approaches. In mice, aldosterone-induced hypokalemia was prevented by simultaneous amiloride infusion, coupled to increased cleavage of α- and γENaC but no effect on NCC. Regression analyses of in vivo data showed a positive correlation between aldosterone/K+ and αENaC but a negative correlation with NCC and pT58-NCC. Ex vivo, exposure of kidney tubules for 21 h to aldosterone increased cleavage of αENaC and γENaC, but no effects were observed on NCC or pT58-NCC. Exposure of tubules to low K+ media reduced αENaC but increased NCC and pT58-NCC. As hypokalemia can enhance cell proliferation markers in the distal convoluted tubule (DCT), we hypothesized that aldosterone infusion would increase proliferating cell nuclear antigen (PCNA) expression. Infusion of aldosterone in mice for 6 days greatly increased PCNA expression in the DCT. Collectively, in vivo and ex vivo data suggest that both aldosterone and K+ can increase ENaC directly. In contrast, the observed increase in abundance and phosphorylation of NCC in aldosterone-infused mice is likely an indirect effect of enhanced ENaC-mediated K+ secretion and subsequent hypokalemia. Thus, it is possible that NCC may only be increased in PA when the condition is associated with hypokalemia.

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“…Altered plasma K + levels per se observed during altered K + intake also modulate NCC abundance and phosphorylation by the modulation of the WNK–SPAK/OSR1 pathway [ 7 ]. To study the contribution of cullins in mediating the K + effects on NCC independent of other systemic factors, we used our extensively characterized ex vivo renal tubule preparations [ 24 , 43 , 44 ] and incubated them in different concentrations of K + (2.5, 3.5, or 6 mM) for 30 min or 24 h ( Figure 4 ). After 30 min, compared with 3.5 mM K + , pT58NCC and phosphorylated SPAK levels were significantly increased and decreased after incubation in low or high K + media, respectively ( Figure 4 A,B).…”

Section: Resultsmentioning

confidence: 99%

Potassium Effects on NCC Are Attenuated during Inhibition of Cullin E3–Ubiquitin Ligases

Murali

Little

Poulsen

et al. 2021

Cells

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The thiazide-sensitive sodium chloride cotransporter (NCC) plays a vital role in maintaining sodium (Na+) and potassium (K+) homeostasis. NCC activity is modulated by with-no-lysine kinases 1 and 4 (WNK1 and WNK4), the abundance of which is controlled by the RING-type E3 ligase Cullin 3 (Cul3) and its substrate adapter Kelch-like protein 3. Dietary K+ intake has an inverse correlation with NCC activity, but the mechanism underlying this phenomenon remains to be fully elucidated. Here, we investigated the involvement of other members of the cullin family in mediating K+ effects on NCC phosphorylation (active form) and abundance. In kidneys from mice fed diets varying in K+ content, there were negative correlations between NCC (phosphorylated and total) and active (neddylated) forms of cullins (Cul1, 3, 4, and 5). High dietary K+ effects on phosphorylated NCC were attenuated in Cul3 mutant mice (CUL3-Het/Δ9). Short-term (30 min) and long-term (24 h) alterations in the extracellular K+ concentration did not affect cullin neddylation levels in ex vivo renal tubules. In the short term, the ability of high extracellular K+ to decrease NCC phosphorylation was preserved in the presence of MLN4924 (pan-cullin inhibitor), but the response to low extracellular K+ was absent. In the long term, MLN4924 attenuated the effects of high extracellular K+ on NCC phosphorylation, and responses to low extracellular K+ were absent. Our data suggest that in addition to Cul3, other cullins are involved in mediating the effects of K+ on NCC phosphorylation and abundance.

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Activation of the kidney sodium chloride cotransporter by the β2-adrenergic receptor agonist salbutamol increases blood pressure

Cited by 18 publications

References 67 publications

Activation of the Thiazide-Sensitive Sodium-Chloride Cotransporter by Beta3-Adrenoreceptor in the Distal Convoluted Tubule

Activation of the Thiazide-Sensitive Sodium-Chloride Cotransporter by Beta3-Adrenoreceptor in the Distal Convoluted Tubule

Dissecting the Effects of Aldosterone and Hypokalemia on the Epithelial Na+ Channel and the NaCl Cotransporter

Potassium Effects on NCC Are Attenuated during Inhibition of Cullin E3–Ubiquitin Ligases

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