Reducing YAP expression in <i>Pkd1</i> mutant mice does not improve the cystic phenotype

Formica, Chiara; Kunnen, Sandra; Dauwerse, Johannes G.; Mullick, Adam E.; Dijkstra, Kyra L.; Scharpfenecker, Marion; Peters, Dorien J.M.

doi:10.1111/jcmm.15512

Cited by 4 publications

(4 citation statements)

References 16 publications

(38 reference statements)

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“…Crucially, these effects were reversed with the inhibition of RhoA signaling ( 147 ). However, more recently, the involvement of transcriptionally-active YAP in ADPKD pathogenesis was disputed ( 148 ).…”

Section: Renal Ciliopathies: Molecular Mechanisms Of Disease and Acti...mentioning

confidence: 99%

Primary cilia and actin regulatory pathways in renal ciliopathies

Kalot,

Sentell,

Kitzler

et al. 2024

Front. Nephrol.

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Ciliopathies are a group of rare genetic disorders caused by defects to the structure or function of the primary cilium. They often affect multiple organs, leading to brain malformations, congenital heart defects, and anomalies of the retina or skeletal system. Kidney abnormalities are among the most frequent ciliopathic phenotypes manifesting as smaller, dysplastic, and cystic kidneys that are often accompanied by renal fibrosis. Many renal ciliopathies cause chronic kidney disease and often progress to end-stage renal disease, necessitating replacing therapies. There are more than 35 known ciliopathies; each is a rare hereditary condition, yet collectively they account for a significant proportion of chronic kidney disease worldwide. The primary cilium is a tiny microtubule-based organelle at the apex of almost all vertebrate cells. It serves as a “cellular antenna” surveying environment outside the cell and transducing this information inside the cell to trigger multiple signaling responses crucial for tissue morphogenesis and homeostasis. Hundreds of proteins and unique cellular mechanisms are involved in cilia formation. Recent evidence suggests that actin remodeling and regulation at the base of the primary cilium strongly impacts ciliogenesis. In this review, we provide an overview of the structure and function of the primary cilium, focusing on the role of actin cytoskeleton and its regulators in ciliogenesis. We then describe the key clinical, genetic, and molecular aspects of renal ciliopathies. We highlight what is known about actin regulation in the pathogenesis of these diseases with the aim to consider these recent molecular findings as potential therapeutic targets for renal ciliopathies.

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Section: Renal Ciliopathies: Molecular Mechanisms Of Disease and Acti...mentioning

confidence: 99%

Primary cilia and actin regulatory pathways in renal ciliopathies

Kalot,

Sentell,

Kitzler

et al. 2024

Front. Nephrol.

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“…Fasudil reversed YAP activation and suppressed renal disease progression [ 48 ]. In other CKO mice, reducing YAP expression with an antisense oligonucleotide did not ameliorate renal cystic disease; however, it did overexpress the downstream targets of the WNT and TGF-β pathways, Myc, Acta2, and Vim [ 49 ]. Further studies on the role of YAP in PKD progression deserve serious consideration.…”

Section: Genetically Modified Modelsmentioning

confidence: 99%

Review of the Use of Animal Models of Human Polycystic Kidney Disease for the Evaluation of Experimental Therapeutic Modalities

Nagao

Yamaguchi

2023

JCM

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Autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, and nephronophthisis are hereditary disorders with the occurrence of numerous cysts in both kidneys, often causing chronic and end-stage renal failure. Animal models have played an important role in recent advances in research not only on disease onset and progressive mechanisms but also on the development of therapeutic interventions. For a long time, spontaneous animal models have been used as the primary focus for human diseases; however, after the identification of the nucleotide sequence of the responsible genes, PKD1, PKD2, PKHD1, and NPHPs, various types of genetically modified models were developed by genetic and reproductive engineering techniques and played the leading role in the research field. In this review, we present murine models of hereditary renal cystic diseases, discussing their potential benefits in the development of therapeutic strategies.

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“…In this context, it is proposed that ADPKD and ARPKD arise from decreased LATS1/2 phosphorylation and increased YAP/TAZ transcriptional activity, while conversely increased LATS1/2 signaling and reduced cellular proliferation underlie the NPH forms [reviewed in (10)]. Whether in fact, unbalanced Hippo signaling is responsible for these differences remains to be determined (17).…”

Section: Introductionmentioning

confidence: 99%

“… 10 ). Whether unbalanced Hippo signaling is in fact responsible for these differences remains to be determined ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

SCF-SKP2 E3 ubiquitin ligase links mTORC1/ER stress/ISR with YAP activation in murine renal cystogenesis

Panda¹,

Xiu-juan²,

Zhang³

et al. 2022

Journal of Clinical Investigation

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The Hippo pathway nuclear effector Yes-associated protein 1 (YAP) potentiates the progression of polycystic kidney disease (PKD) arising from ciliopathies. The mechanisms underlying the increase in YAP expression and transcriptional activity in PKD remain obscure. We observed that in kidneys from mice with juvenile cystic kidney (jck) ciliopathy, the aberrant hyperactivity of mechanistic target of rapamycin complex 1 (mTORC1) driven by ERK1/2 and PI3K/AKT cascades induced endoplasmic reticulum (ER) proteotoxic stress. To reduce it by reprogramming translation, the protein kinase R-like ER kinase (PERK)-eukaryotic initiation factor 2α (eIF2α) arm of the integrated stress response (ISR) was activated. PERK-mediated phosphorylation of eIF2α drove the selective translation of activating transcription factor 4 (ATF4), potentiating YAP expression. In parallel, YAP underwent K63-linked polyubiquitination by SCF-S-phase kinase-associated protein 2 (SKP2) E3 ubiquitin ligase, a Hippo-independent, nonproteolytic ubiquitination that enhances YAP nuclear trafficking and transcriptional activity in cancer cells. Defective ISR cellular adaptation to ER stress in eIF2α-phosphorylation-deficient jck mice further augmented YAP-mediated transcriptional activity and renal cyst growth. Conversely, pharmacological tuning down of ER stress-ISR activity and SKP2 expression in jck mice by administration of tauroursodeoxycholic acid (TUDCA) or tolvaptan, impeded these processes. Restoring ER homeostasis, and/or interfering with the SKP2-YAP interaction represent novel potential therapeutic avenues for stemming the progression of renal cystogenesis.

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Reducing YAP expression in Pkd1 mutant mice does not improve the cystic phenotype

Cited by 4 publications

References 16 publications

Primary cilia and actin regulatory pathways in renal ciliopathies

Primary cilia and actin regulatory pathways in renal ciliopathies

Review of the Use of Animal Models of Human Polycystic Kidney Disease for the Evaluation of Experimental Therapeutic Modalities

SCF-SKP2 E3 ubiquitin ligase links mTORC1/ER stress/ISR with YAP activation in murine renal cystogenesis

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