Renal TNFα activates the WNK phosphorylation cascade and contributes to salt-sensitive hypertension in chronic kidney disease

Furusho, Taisuke; Sohara, Eisei; Mandai, Shintaro; Kikuchi, Hiroaki; Takahashi, Naohiro; Fujimaru, Takuya; Hashimoto, Hiroko; Arai, Yohei; Ando, Fumiaki; Zeniya, Moko; Mori, Takayasu; Susa, Koichiro; Isobe, Kiyoshi; Nomura, Naohiro; Yamamoto, Kohei; Okado, Tomokazu; Rai, Tatemitsu; Uchida, Shinichi

doi:10.1016/j.kint.2019.11.021

Cited by 37 publications

(29 citation statements)

References 64 publications

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“…We found that NCC, but not ENaC, plays an important role in the regulation of urinary sodium excretion and subsequent osmotic diuresis. Consistent with our observations, NCC activation drives salt-sensitive hypertension in chronic kidney disease 30 , while other groups suggest that ENaC activity is key to the development of hypertension in spontaneously hypertensive rats 58 , indicative of disease-speci c involvement.…”

Section: Discussionsupporting

confidence: 92%

“…SPAK-NCC pathway activation has been reported to occur through a variety of mechanisms, including aldosterone, angiotensin II, and insulin signaling as well as extracellular K and oxidative stress [30][31][32][33][34] . We examined whether aldosterone and angiotensin II, which are generally implicated in the effects of salt loading, are indeed involved.…”

Section: Angiotensin II In the Kidney Activates The Spak-ncc Pathwaymentioning

confidence: 99%

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Dietary Salt With Nitric Oxide Deficiency Induces Nocturnal Polyuria via Hyperactivation of Intrarenal Angiotensin Ⅱ-SPAK-NCC Pathway

Sekii

Kiuchi

Takezawa

et al. 2021

Preprint

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Nocturnal polyuria is the most frequent cause of nocturia, a common disease associated with a compromised quality of life and increased mortality. Its pathogenesis is complex, and the detailed underlying mechanism remains unknown. Herein, we report that concomitant intake of a high-salt diet and reduced nitric oxide (NO) production achieved through Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) administration in mice resulted in nocturnal polyuria recapitulating the clinical features in humans. High salt intake under reduced NO production overactivated the angiotensin II-SPAK (STE20/SPS1-related proline–alanine-rich protein kinase)-NCC (sodium chloride co-transporter) pathway in the kidney, resulting in the insufficient excretion of sodium during the day and its excessive excretion at night. Excessive Na excretion at night in turn leads to nocturnal polyuria due to osmotic diuresis. Our study identified a central role for the intrarenal angiotensin II-SPAK-NCC pathway in the pathophysiology of nocturnal polyuria, highlighting its potential as a promising therapeutic target.

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Section: Discussionsupporting

confidence: 92%

Section: Angiotensin II In the Kidney Activates The Spak-ncc Pathwaymentioning

confidence: 99%

Dietary Salt With Nitric Oxide Deficiency Induces Nocturnal Polyuria via Hyperactivation of Intrarenal Angiotensin Ⅱ-SPAK-NCC Pathway

Sekii

Kiuchi

Takezawa

et al. 2021

Preprint

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“…Although the rationale to inhibit WNK1 signaling in our study was based on a clinical observation, other molecular mechanisms likely promote WNK1 upregulation in RVD. First, WNK1 levels are increased by tumor necrosis factor- (TNF) via reducing expression of NEDD4-2 E3-ligase (neuronal precursor cell-expressed developmentally downregulated 4-2 E3-ubiquitin ligase), a protein that degrades WNK1 in kidney cells (43). This is directly relevant to RVD because TNF levels increase with the severity of RVD in rodent PAH (44).…”

Section: Discussionmentioning

confidence: 99%

With No Lysine Kinase 1 Promotes Right Ventricular Dysfunction Via Glucotoxicity

Prisco

Eklund

Thenappan

et al. 2021

Preprint

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Objectives: Investigate how WNK1 inhibition modulates glucotoxicity, mitochondrial/peroxisomal protein regulation and metabolism, and right ventricular (RV) function in pulmonary arterial hypertension (PAH). Determine how hypochloremia impacts RV function in PAH patients. Background: In PAH-induced RV failure, GLUT1/GLUT4 expression is elevated, which increases glucose uptake and glycolytic flux to compensate for mitochondrial dysfunction. However, the resultant consequences of the glucose-mediated post-translational modifications (PTM), protein O-GlcNAcylation/glycation in RV failure are understudied. WNK1, a chloride-sensitive kinase, increases GLUT1/GLUT4 expression in skeletal muscle, but its regulation in RV dysfunction is unexplored. Methods: Rats were treated with WNK463 (small molecule WNK inhibitor) or vehicle starting two weeks after monocrotaline injection. Immunoblots quantified protein abundance/PTMs. Mitochondrial/peroxisomal proteomics and global metabolomics evaluated glucose metabolism and mitochondrial/peroxisomal function. Pulmonary vascular and cardiac histology, echocardiography, and pressure-volume loop analysis quantified RV function and PAH severity. Finally, the relationship between hypochloremia, a WNK1-activating state, and RV function was evaluated in 217 PAH patients. Results: WNK463 decreased WNK1/GLUT1/GLUT4 expression, normalized glucose metabolite levels, which dampened excess protein O-GlcNAcylation/glycation. Integration of RV mitochondrial/peroxisomal proteomics and metabolomics identified fatty acid oxidation (FAO) as the most dysregulated metabolic pathway. WNK463 enhanced FAO as demonstrated by increased expression of mitochondrial FAO proteins and normalization of RV acylcarnitines. WNK463 reduced glutaminolysis induction and lipotoxicity, two secondary consequences of diminished FAO. WNK463 augmented RV systolic and diastolic function independent of pulmonary vascular disease severity. In PAH patients, hypochloremia resulted in more severe RV dysfunction. Conclusions: WNK463 combated RV glucotoxicity and impaired FAO, which directly improved RV function.

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“…NEDD4-2 binds to the PY motifs of WNK1, ubiquitylating WNK1 and targeting it for proteasomal degradation [ 46 ]. Dysregulation of NEDD4-2 has been implicated in the pathophysiology of salt-sensitive hypertension in a model of chronic kidney disease, which resulted in NCC activation through WNK1/SPAK [ 47 ]. In a recent study, Wu et al reported that NEDD4-2 modulated NCC levels through a mechanism involving basolateral K + channel Kir4.1 (KCNJ10) [ 48 ].…”

Section: Role Of Ups In the Regulation Of Tubular Function In The mentioning

confidence: 99%

Role of the Ubiquitin Proteasome System in the Regulation of Blood Pressure: A Review

Hirohama

Ishizawa

Shibata

2020

IJMS

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The kidney and the vasculature play crucial roles in regulating blood pressure. The ubiquitin proteasome system (UPS), a multienzyme process mediating covalent conjugation of the 76-amino acid polypeptide ubiquitin to a substrate protein followed by proteasomal degradation, is involved in multiple cellular processes by regulating protein turnover in various tissues. Increasing evidence demonstrates the roles of UPS in blood pressure regulation. In the kidney, filtered sodium is reabsorbed through diverse sodium transporters and channels along renal tubules, and studies conducted till date have provided insights into the complex molecular network through which ubiquitin ligases modulate sodium transport in different segments. Components of these pathways include ubiquitin ligase neuronal precursor cell-expressed developmentally downregulated 4-2, Cullin-3, and Kelch-like 3. Moreover, accumulating data indicate the roles of UPS in blood vessels, where it modulates nitric oxide bioavailability and vasoconstriction. Cullin-3 not only regulates renal salt reabsorption but also controls vascular tone using different adaptor proteins that target distinct substrates in vascular smooth muscle cells. In endothelial cells, UPS can also contribute to blood pressure regulation by modulating endothelial nitric oxide synthase. In this review, we summarize current knowledge regarding the role of UPS in blood pressure regulation, focusing on renal sodium reabsorption and vascular function.

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Renal TNFα activates the WNK phosphorylation cascade and contributes to salt-sensitive hypertension in chronic kidney disease

Cited by 37 publications

References 64 publications

Dietary Salt With Nitric Oxide Deficiency Induces Nocturnal Polyuria via Hyperactivation of Intrarenal Angiotensin Ⅱ-SPAK-NCC Pathway

Dietary Salt With Nitric Oxide Deficiency Induces Nocturnal Polyuria via Hyperactivation of Intrarenal Angiotensin Ⅱ-SPAK-NCC Pathway

With No Lysine Kinase 1 Promotes Right Ventricular Dysfunction Via Glucotoxicity

Role of the Ubiquitin Proteasome System in the Regulation of Blood Pressure: A Review

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