WNK4 is indispensable for the pathogenesis of pseudohypoaldosteronism type II caused by mutant KLHL3

Susa, Koichiro; Sohara, Eisei; Takahashi, Daichi; Okado, Tomokazu; Rai, Tatemitsu; Uchida, Shinichi

doi:10.1016/j.bbrc.2017.07.121

Cited by 18 publications

(13 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An example is Wnk4 , which is expressed in late PHCs and early HCs ( Fig 3G ). WNK4 is the major regulator of the Na-Cl co-transporter in the kidney, a regulator of adipogenesis and energy metabolism and a causal gene for pseudohypoaldosteronism type II [ 78 – 80 ], but has no known role in chondrocyte hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

Synergistic co-regulation and competition by a SOX9-GLI-FOXA phasic transcriptional network coordinate chondrocyte differentiation transitions

et al. 2018

View full text Add to dashboard Cite

The growth plate mediates bone growth where SOX9 and GLI factors control chondrocyte proliferation, differentiation and entry into hypertrophy. FOXA factors regulate hypertrophic chondrocyte maturation. How these factors integrate into a Gene Regulatory Network (GRN) controlling these differentiation transitions is incompletely understood. We adopted a genome-wide whole tissue approach to establish a Growth Plate Differential Gene Expression Library (GP-DGEL) for fractionated proliferating, pre-hypertrophic, early and late hypertrophic chondrocytes, as an overarching resource for discovery of pathways and disease candidates. De novo motif discovery revealed the enrichment of SOX9 and GLI binding sites in the genes preferentially expressed in proliferating and prehypertrophic chondrocytes, suggesting the potential cooperation between SOX9 and GLI proteins. We integrated the analyses of the transcriptome, SOX9, GLI1 and GLI3 ChIP-seq datasets, with functional validation by transactivation assays and mouse mutants. We identified new SOX9 targets and showed SOX9-GLI directly and cooperatively regulate many genes such as Trps1, Sox9, Sox5, Sox6, Col2a1, Ptch1, Gli1 and Gli2. Further, FOXA2 competes with SOX9 for the transactivation of target genes. The data support a model of SOX9-GLI-FOXA phasic GRN in chondrocyte development. Together, SOX9-GLI auto-regulate and cooperate to activate and repress genes in proliferating chondrocytes. Upon hypertrophy, FOXA competes with SOX9, and control toward terminal differentiation passes to FOXA, RUNX, AP1 and MEF2 factors.

show abstract

Section: Discussionmentioning

confidence: 99%

Synergistic co-regulation and competition by a SOX9-GLI-FOXA phasic transcriptional network coordinate chondrocyte differentiation transitions

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Finally, the ubiquitinated WNK4 protein is degraded by proteasomes. Numerous studies have reported that mutant KLHL3 and Cullin3 molecules may decrease the ubiquitination of WNK4 (24,25). In addition, WNK4 mutations (E562K, Q565E and D561A) (5,13,26) have been reported to inhibit the binding of WNK4 to KLHL3; however, the exact site of ubiquitination in the WNK4 protein remained unclear.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between phosphorylation and ubiquitination is involved in high salt-induced WNK4 expression

Zhao

Lai

et al. 2020

Exp Ther Med

View full text Add to dashboard Cite

“…The disease can be dominant, recessive, or sporadic, depending on the mutated gene. All clinical features respond to low doses of a thiazide-type diuretic and current evidence strongly suggests that an increase in NCC function is the first order event that drives FHHt (16,26,32,64,77).…”

Section: Clinical Syndromes Due To Altered Activity Of Nccmentioning

confidence: 97%

“…The KLHL3 Ϫ/Ϫ model resembles the scenario observed with certain KLHL3 mutations that present a recessive pattern of inheritance, confirming that KLHL3 haploinsufficiency is not enough to produce the disease and that dominant mutations must have a dominant negative effect. Interestingly, elimination of WNK4 in the KLHL3 R528H/ϩ mice (WNK4 Ϫ/Ϫ KLHL3 R528H/ϩ or WNK4 Ϫ/Ϫ KLHL3 R528H/R528H mice) resulted in downregulation of NCC and SPAK, to levels similar to those observed in the WNK4 Ϫ/Ϫ mice (13), despite the fact that these mice showed increased renal WNK1 protein levels (64). This result clearly contrasts with what is observed in WNK4 Ϫ/Ϫ WNK1 ϩ/FHHt mice in which the FHHt phenotype prevails (with high NCC and pNCC) (15), suggesting the KLHL3-R528H mutation has a different effect on the expression of WNK1 than the deletion of a segment of intron 1 of the WNK1 gene.…”

Section: Klhl3 Modelsmentioning

confidence: 98%

Regulation of the renal NaCl cotransporter by the WNK/SPAK pathway: lessons learned from genetically altered animals

Ostrosky-Frid

Castañeda‐Bueno

Gamba

2019

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

The renal thiazide-sensitive NaCl cotransporter (NCC) is the major salt transport pathway in the distal convoluted tubule of the mammalian nephron. NCC activity is critical for modulation of arterial blood pressure and serum potassium levels. Reduced activity of NCC in genetic diseases results in arterial hypotension and hypokalemia, while increased activity results in genetic diseases featuring hypertension and hyperkalemia. Several hormones and physiological conditions modulate NCC activity through a final intracellular complex pathway involving kinases and ubiquitin ligases. A substantial amount of work has been conducted to understand this pathway in the last 15 years, but advances over the last three years have helped to begin to understand how these regulatory proteins interact with each other and modulate the activity of this important cotransporter. In this review, we present the current model of NCC regulation by the CUL3/KELCH3-WNK-SPAK pathway. We present a review of all genetically altered mice that have been used to translate most of the proposals made from in vitro experiments into in vivo observations that have helped to elucidate the model at the physiological level. Many questions have been resolved, but some others will require further models to be constructed. In addition, unexpected observations in mice have raised new questions and identified regulatory pathways that were previously unknown.

show abstract

WNK4 is indispensable for the pathogenesis of pseudohypoaldosteronism type II caused by mutant KLHL3

Cited by 18 publications

References 28 publications

Synergistic co-regulation and competition by a SOX9-GLI-FOXA phasic transcriptional network coordinate chondrocyte differentiation transitions

Synergistic co-regulation and competition by a SOX9-GLI-FOXA phasic transcriptional network coordinate chondrocyte differentiation transitions

Crosstalk between phosphorylation and ubiquitination is involved in high salt-induced WNK4 expression

Regulation of the renal NaCl cotransporter by the WNK/SPAK pathway: lessons learned from genetically altered animals

Contact Info

Product

Resources

About