Decreased KLHL3 expression is involved in the activation of WNK-OSR1/SPAK-NCC cascade in type 1 diabetic mice

Guo, Qi; Zhang, Ya; Jiang, Gengru; Zhang, Chong

doi:10.1007/s00424-020-02509-8

Cited by 10 publications

(9 citation statements)

References 41 publications

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“…Recent work from the Fenton group suggests neddylation of several cullins, including CUL3 changes in dietary K + intake in mice, 42 (preprint) pointing to a possible role for modulation of JAB1 activity under normal physiologic conditions. Dysregulation of CUL3 neddylation may also contribute to diabetic kidney disease, because KLHL3 abundance is lower in db/db diabetic mice, 14 in streptozotocin-induced type 1 diabetic mice, 15 and in a mouse model of pre-eclampsia, 43 with increased NCC phosphorylation observed in all three models. We also reported that renal tubular Cul3 −/− mice develop renal fibrosis, and that lower CUL3 abundance is observed in several mouse renal injury models 44 .…”

Section: Discussionmentioning

confidence: 99%

“…This cycling of NEDD8 addition/removal (“neddylation”/“deneddylation”) is essential for the stability and activity of the CRL, and has been shown to be physiologically important in multiple organs including the heart, 11 the brain, 12 and the immune system 13 . In the kidney, recent evidence from studies in mice suggests that cullin neddylation status changes in response to dietary potassium, 6 or in models of diabetes 14 , 15 . Two types of FHHt-causing CUL3 mutation have been identified.…”

mentioning

confidence: 99%

“…13 In the kidney, recent evidence from studies in mice suggests that cullin neddylation status changes in response to dietary potassium, 6 or in models of diabetes. 14,15 Two types of Cycling of NEDD8 addition (neddylation) and removal (deneddylation is essential to maintain CRL stability and activity. (Right) In FHHt, WNK4 accumulates, resulting in hyperactivation of NCC.…”

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confidence: 99%

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Combined Kelch-like 3 and Cullin 3 Degradation is a Central Mechanism in Familial Hyperkalemic Hypertension in Mice

Maeoka

Ferdaus

Cornelius

et al. 2022

JASN

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Background: Mutations in the ubiquitin ligase scaffold protein Cullin 3 (CUL3) cause the disease Familial Hyperkalemic Hypertension (FHHt). In the kidney, mutant CUL3 (CUL3-Δ9) increases abundance of With-No-Lysine [K] Kinase 4 (WNK4), inappropriately activating Sterile 20/SPS-1-related proline/alanine-rich kinase (SPAK), which then phosphorylates and hyperactivates the Na+-Cl- cotransporter (NCC). The precise mechanism by which CUL3-Δ9 causes FHHt has been unclear. We tested the hypothesis that reduced abundances of CUL3 and of Kelch-like 3 (KLHL3), the CUL3 substrate adaptor for WNK4, are mechanistically important. Since JAB1, an enzyme that inhibits CUL3 activity by removing the ubiquitin-like protein NEDD8, cannot interact with CUL3-Δ9, we also determined whether Jab1 disruption mimicked the effects of CUL3-Δ9 expression. Methods: We used an inducible renal tubule-specific system to generate several mouse models expressing CUL3-Δ9, mice heterozygous for both CUL3 and KLHL3 (Cul3+/−/Klhl3+/−), and mice with short-term Jab1 disruption (to avoid renal injury associated with long-term disruption). Results: Renal KLHL3 was higher in Cul3−/− mice, but lower in Cul3−/−/Δ9 mice and in the Cul3+/−/Δ9 FHHt model, suggesting KLHL3 is a target for both WT and mutant CUL3. Cul3+/−/Klhl3+/− mice displayed increased WNK4-SPAK activation and phospho-NCC abundance, and an FHHt-like phenotype with increased plasma [K+] and salt-sensitive blood pressure. Short-term Jab1 disruption in mice lowered abundances of CUL3 and KLHL3, and increased abundances of WNK4 and phospho-NCC. Conclusions:Jab1-/- mice and Cul3+/−/Klhl3+/− mice recapitulated the effects of CUL3-Δ9 expression on WNK4-SPAK-NCC. Our data suggest that degradation of both KLHL3 and CUL3 plays a central mechanistic role in CUL3-Δ9-mediated FHHt.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Combined Kelch-like 3 and Cullin 3 Degradation is a Central Mechanism in Familial Hyperkalemic Hypertension in Mice

Maeoka

Ferdaus

Cornelius

et al. 2022

JASN

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“…Notably, it has been shown that PKC-mediated phosphorylation of KLHL3 at S433 inactivates KLHL3, increasing NCC activity in db/db diabetic mice and this was attenuated by iSGLT2. 48,49 The authors attributed increased activity of NCC to PKC activation, which is associated with hyperglycemia and, thus, the metabolic improvement with iSGLT2 reduced NCC phosphorylation. We believe that their observation and ours in NCC activity by iSGLT2 treatment are due to different models and mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Glucose/Fructose Delivery to the Distal Nephron Activates the Sodium-Chloride Cotransporter via the Calcium-Sensing Receptor

Bahena-López

Rojas‐Vega

Chávez-Canales

et al. 2022

JASN

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Background: The calcium sensing receptor (CaSR) in the distal convoluted tubule (DCT) activates the NaCl cotransporter (NCC). Glucose acts as a positive allosteric modulator of the CaSR. Under physiological conditions, no glucose is delivered to the DCT and fructose delivery depends on consumption. We hypothesized that glucose/fructose delivery to the DCT modulates the CaSR in a positive allosteric way, activating the WNK4-SPAK-NCC pathway and thus increasing salt retention. Methods: We evaluated the effect of glucose/fructose arrival to the distal nephron on the CaSR-WNK4-SPAK-NCC pathway using HEK-293 cells, C57BL/6 and WNK4-knockout mice, ex vivo perfused kidneys, and healthy humans. Results: HEK-293 cells exposed to glucose/fructose increased SPAK phosphorylation in a WNK4 and CaSR dependent manner. C57BL/6 mice exposed to fructose or a single dose of dapagliflozin to induce transient glycosuria showed increased activity of the WNK4-SPAK-NCC pathway. The calcilytic NPS2143 ameliorated this effect, which was not observed in WNK4-KO mice. C57BL/6 mice treated with fructose or dapagliflozin showed markedly increased natriuresis after thiazide challenge. Ex vivo rat kidney perfused with glucose above physiological threshold levels for proximal reabsorption showed increased NCC and SPAK phosphorylation. NPS2143 prevented this effect. In healthy volunteers cinacalcet administration, fructose intake, or a single dose of dapagliflozin increased SPAK and NCC phosphorylation in urinary extracellular vesicles. Conclusions: Glycosuria or fructosuria were associated with increased NCC, SPAK, and WNK4 phosphorylation in a CaSR-dependent manner.

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“…Pathways include hemostasis [57], neutrophil degranulation [58], immune system [59] and cytokine signaling in immune system [60] are responsible for progression of GDM. LGR5 [61], GREM1 [62], GLRA3 [63], NEUROD4 [64], CYP2J2 [65], KCNH6 [66], LBP (lipopolysaccharide binding protein) [67], CXCL14 [68], RGN (regucalcin) [69], NPY2R [70], SERPINB13 [71], WNT5A [72], EDA (ectodysplasin A) [73], HSD11B2 [74], ACVR1C [75], NEUROD1 [76], SLIT2 [77], PPARGC1A [78], IGF1 [79], OSR1 [80], CYP46A1 [81], TLR3 [82], BMP7 [83], SELP (selectin P) [84], HLA-A [85], NOTCH2 [86], LRP1 [87], CLU (clusterin) [88], FCN1 [89], CDKN1A [90], SMAD3 [91], HLA-E [92], PTPRC (protein tyrosine phosphatase receptor type C) [93], MYH9 [94], JAK3 [95], IL6R [96], TIMP1 [97], DOCK8 [98], TNFRSF1B [99], ITGAL (integrin subunit alpha L) [100], CD47 [101], RARA (retinoic acid receptor alpha) [102], DGKD (diacylglycerol kinase delta) [103], PLEK (pleckstrin) [104], PREX1 [105], BSCL2 [106], PANX1 [107], IRF7 [108], NOTCH1 [109], STIM1 [110], TRIM13 [111], LRBA (LPS responsive beige-like anchor protein) [112], CXCR4 [113], MDM4 [114], MYO9B [115] and PDE5A [116] were revealed to be expressed in diabetes mellitus, but these genes might be novel targets for GDM. SIX1 [117], GREM1 [118], GHRHR (growth hormone releasing hormone receptor) [119], GPR37L1 [120], CYP2J2 [121], AQP4 [122], ROS1 [123], LBP (lipopolysaccharide binding protein) [124], SGCD (sarcoglycan delta) [125], CXCL14 [126], RGN...…”

Section: Discussionmentioning

confidence: 99%

Identification of differentially expressed genes and signaling pathways in gestational diabetes mellitus by integrated bioinformatics analysis

Vastrad¹,

Vastrad²

2021

Preprint

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Gestational diabetes mellitus (GDM) is a metabolic disorder during pregnancy. Numerous biomarkers have been identified that are linked with the occurrence and development of GDM. The aim of this investigation was to identify differentially expressed genes (DEGs) in GDM using a bioinformatics approach to elucidate their molecular pathogenesis. GDM associated expression profiling by high throughput sequencing dataset (GSE154377) was obtained from Gene Expression Omnibus (GEO) database including 28 normal pregnancy samples and 33 GDM samples. DEGs were identified using DESeq2. The gene ontology (GO) and REACTOME pathway enrichments of DEGs were performed by g:Profiler. Protein-protein interaction (PPI) networks were assembled with Cytoscape software and separated into modules using the PEWCC1 algorithm. MiRNA-hub gene regulatory network and TF-hub gene regulatory network were performed with the miRNet database and NetworkAnalyst database. Receiver Operating Characteristic (ROC) analyses was conducted to validate the hub genes. A total of 953 DEGs were identified, of which 478 DEGs were up regulated and 475 DEGs were down regulated. Furthermore, GO and REACTOME pathway enrichment analysis demonstrated that these DEGs were mainly enriched in multicellular organismal process, cell activation, formation of the cornified envelope and hemostasis. TRIM54, ELAVL2, PTN, KIT, BMPR1B, APP, SRC, ITGA4, RPA1 and ACTB were identified as key genes in the PPI network, miRNA-hub gene regulatory network and TF-hub gene regulatory network. TRIM54, ELAVL2, PTN, KIT, BMPR1B, APP, SRC, ITGA4, RPA1 and ACTB in GDM were validated using ROC analysis. This investigation provides further insights into the molecular pathogenesis of GDM, which might facilitate the diagnosis and treatment of GDM.

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Decreased KLHL3 expression is involved in the activation of WNK-OSR1/SPAK-NCC cascade in type 1 diabetic mice

Cited by 10 publications

References 41 publications

Combined Kelch-like 3 and Cullin 3 Degradation is a Central Mechanism in Familial Hyperkalemic Hypertension in Mice

Combined Kelch-like 3 and Cullin 3 Degradation is a Central Mechanism in Familial Hyperkalemic Hypertension in Mice

Glucose/Fructose Delivery to the Distal Nephron Activates the Sodium-Chloride Cotransporter via the Calcium-Sensing Receptor

Identification of differentially expressed genes and signaling pathways in gestational diabetes mellitus by integrated bioinformatics analysis

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