H,K-ATPase type 2 contributes to salt-sensitive hypertension induced by K+ restriction

Walter, Christine; Tanfous, M. Ben; Igoudjil, Katia; Salhi, Amel; Escher, Geneviève; Crambert, Gilles

doi:10.1007/s00424-016-1872-z

Cited by 16 publications

(15 citation statements)

References 45 publications

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“…Plasma K + and Na + at 4 days of LKD were similar in both genotypes (Figure 1, F and G). Similar to recent observations by Walter et al, 23 urinary Na + excretion transiently increased under LKD in both groups (Supplemental Figure 1A) but was recovered after 2 weeks ( Figure 2D). This transient LKD-induced natriuresis is most likely because of diminished aldosterone and reduction of ENaC activity, 33,34 and diminution of NKCC2 expression/ activity attributed to a reduction in filtered K + .…”

Section: The Early Adaptation To K + Deficiency Is Independent Of Rensupporting

confidence: 90%

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Renal Tubular Ubiquitin-Protein Ligase NEDD4-2 Is Required for Renal Adaptation during Long-Term Potassium Depletion

Al‐Qusairi

Basquin

Roy

et al. 2017

JASN

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Adaptation of the organism to potassium (K) deficiency requires precise coordination among organs involved in K homeostasis, including muscle, liver, and kidney. How the latter performs functional and molecular changes to ensure K retention is not well understood. Here, we investigated the role of ubiquitin-protein ligase NEDD4-2, which negatively regulates the epithelial sodium channel (ENaC), Na/Cl cotransporter (NCC), and with no-lysine-kinase 1 (WNK1). After dietary K restriction for 2 weeks, compared with control littermates, inducible renal tubular NEDD4-2 knockout ( ) mice exhibited severe hypokalemia and urinary K wasting. Notably, expression of the ROMK K channel did not change in the distal convoluted tubule and decreased slightly in the cortical/medullary collecting duct, whereas BK channel abundance increased in principal cells of the connecting tubule/collecting ducts. However, K restriction also enhanced ENaC expression in mice, and treatment with the ENaC inhibitor, benzamil, reversed excessive K wasting. Moreover, K restriction increased WNK1 and WNK4 expression and enhanced SPAK-mediated NCC phosphorylation in mice, with no change in total NCC. We propose a mechanism in which NEDD4-2 deficiency exacerbates hypokalemia during dietary K restriction primarily through direct upregulation of ENaC, whereas increased BK channel expression has a less significant role. These changes outweigh the compensatory antikaliuretic effects of diminished ROMK expression, increased NCC phosphorylation, and enhanced WNK pathway activity in the distal convoluted tubule. Thus, NEDD4-2 has a crucial role in K conservation through direct and indirect effects on ENaC, distal nephron K channels, and WNK signaling.

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Section: The Early Adaptation To K + Deficiency Is Independent Of Rensupporting

confidence: 90%

“…Nevertheless, NCC is stimulated because of the aldosterone-independent effect of hypokalemia. 11,22,23 One can reasonably assume that mechanisms that interfere with K + secretion are important as well, and that such inhibitory mechanisms might involve NEDD4-2.…”

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confidence: 99%

Renal Tubular Ubiquitin-Protein Ligase NEDD4-2 Is Required for Renal Adaptation during Long-Term Potassium Depletion

Al‐Qusairi

Basquin

Roy

et al. 2017

JASN

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“…However, the phenotypic complexity of the HKA1-null mice and the possible contribution of other mechanisms make it difficult to interpret all these findings. Our laboratory has also shown recently that during K + depletion, the absence of HKA2 hinders the inhibition of ENaC and interferes with the regulation of AQP2 (95).…”

Section: Interactions Between Principal Cells and Type A Cellsmentioning

confidence: 88%

Versatility of NaCl transport mechanisms in the cortical collecting duct

Edwards

Crambert

2017

American Journal of Physiology-Renal Physiology

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The cortical collecting duct (CCD) forms part of the aldosterone-sensitive distal nephron and plays an essential role in maintaining the NaCl balance and acid-base status. The CCD epithelium comprises principal cells as well as different types of intercalated cells. Until recently, transcellular Na transport was thought to be restricted to principal cells, whereas (acid-secreting) type A and (bicarbonate-secreting) type B intercalated cells were associated with the regulation of acid-base homeostasis. This review describes how this traditional view has been upended by several discoveries in the past decade. A series of studies has shown that type B intercalated cells can mediate electroneutral NaCl reabsorption by a mechanism involving Na-dependent and Na-independent Cl/[Formula: see text] exchange, and that is energetically driven by basolateral vacuolar H-ATPase pumps. Other research indicates that type A intercalated cells can mediate NaCl secretion, through a bumetanide-sensitive pathway that is energized by apical H,K-ATPase type 2 pumps operating as Na/K exchangers. We also review recent findings on the contribution of the paracellular route to NaCl transport in the CCD. Last, we describe cross-talk processes, by which one CCD cell type impacts Na/Cl transport in another cell type. The mechanisms that have been identified to date demonstrate clearly the interdependence of NaCl and acid-base transport systems in the CCD. They also highlight the remarkable versatility of this nephron segment.

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“…In a study of mouse gastric and colonic mucosa, the pharmacological profile of each isoform was studied and confirmed that HK␣ 1 is inhibited by Sch-28080; whereas HK␣ 2 was Sch-28080 and ouabain insensitive (23). Previous studies have suggested that H ϩ ,K ϩ -ATPases function in the regulation of Na ϩ balance (4,19,29). Our laboratory has shown that the long-acting mineralocorticoid desoxycorticosterone pivilate (DOCP) induced an increase in H ϩ ,K ϩ -ATPase-mediated proton secretion in A-type intercalated cells of the cortical CD from WT mice (4).…”

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confidence: 81%

ENaC activity in the cortical collecting duct of HKα₁ H⁺,K⁺-ATPase knockout mice is uncoupled from Na⁺ intake

Mironova

Lynch

Berman

et al. 2017

American Journal of Physiology-Renal Physiology

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Modulation of the epithelial Na channel (ENaC) activity in the collecting duct (CD) is an important mechanism for normal Na homeostasis. ENaC activity is inversely related to dietary Na intake, in part due to inhibitory paracrine purinergic regulation. Evidence suggests that H,K-ATPase activity in the CD also influences Na excretion. We hypothesized that renal H,K-ATPases affect Na reabsorption by the CD by modulating ENaC activity. ENaC activity in HKα H,K-ATPase knockout (HKα) mice was uncoupled from Na intake. ENaC activity on a high-Na diet was greater in the HKα mice than in WT mice. Moreover, dietary Na content did not modulate ENaC activity in the HKα mice as it did in WT mice. Purinergic regulation of ENaC was abnormal in HKα mice. In contrast to WT mice, where urinary [ATP] was proportional to dietary Na intake, urinary [ATP] did not increase in response to a high-Na diet in the HKα mice and was significantly lower than in the WT mice. HKα mice fed a high-Na diet had greater Na retention than WT mice and had an impaired dipsogenic response. These results suggest an important role for the HKα subunit in the regulation of purinergic signaling in the CD. They are also consistent with HKα-containing H,K-ATPases as important components for the proper regulation of Na balance and the dipsogenic response to a high-salt diet. Such observations suggest a previously unrecognized element in Na regulation in the CD.

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H,K-ATPase type 2 contributes to salt-sensitive hypertension induced by K+ restriction

Cited by 16 publications

References 45 publications

Renal Tubular Ubiquitin-Protein Ligase NEDD4-2 Is Required for Renal Adaptation during Long-Term Potassium Depletion

Renal Tubular Ubiquitin-Protein Ligase NEDD4-2 Is Required for Renal Adaptation during Long-Term Potassium Depletion

Versatility of NaCl transport mechanisms in the cortical collecting duct

ENaC activity in the cortical collecting duct of HKα₁ H⁺,K⁺-ATPase knockout mice is uncoupled from Na⁺ intake

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H,K-ATPase type 2 contributes to salt-sensitive hypertension induced by K+ restriction

Cited by 16 publications

References 45 publications

Renal Tubular Ubiquitin-Protein Ligase NEDD4-2 Is Required for Renal Adaptation during Long-Term Potassium Depletion

Renal Tubular Ubiquitin-Protein Ligase NEDD4-2 Is Required for Renal Adaptation during Long-Term Potassium Depletion

Versatility of NaCl transport mechanisms in the cortical collecting duct

ENaC activity in the cortical collecting duct of HKα1 H+,K+-ATPase knockout mice is uncoupled from Na+ intake

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ENaC activity in the cortical collecting duct of HKα₁ H⁺,K⁺-ATPase knockout mice is uncoupled from Na⁺ intake