c-Met and NF-κB–Dependent Overexpression of Wnt7a and -7b and Pax2 Promotes Cystogenesis in Polycystic Kidney Disease

Qin, Shan; Taglienti, Mary; Cai, Lei; Zhou, Jing; Kreidberg, Jordan A.

doi:10.1681/asn.2011030277

Cited by 58 publications

(52 citation statements)

References 66 publications

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“…The first main finding of this study is that a diverse array of NF-κB proteins, including p50, P-p105, p65, RelB and c-rel, is present in LPK kidneys. The localization of these NF-κB proteins to the CECs in LPK kidneys concurs with previous in vivo studies of Pkd1 -/-and PKD2 mice [22,23] . Notably, p65, p50 and RelB were predominantly localized to the cytoplasm rather than to the nuclei of CECs.…”

Section: Discussionsupporting

confidence: 90%

“…The chronological order of these events may suggest that NF-κB activation contributes to cyst expansion via the upregulation of cell proliferation and interstitial inflammation. Qin et al [23] found that NF-κB inhibition decreases cyst growth in kidney explants, supporting the theory that cyst growth is NF-κB-dependent. Secondly, western blotting indicated that NF-κB protein levels were elevated in mid-to late-stage disease, coinciding with the elevations in TNFa and CCL2 at weeks 10 and 20.…”

mentioning

confidence: 73%

“…Taking into account previous studies, NF-κB upregulation has now been identified in human PKD or animal models that possess mutations in PKD1, PKD2, PKHD1, and NEK8, suggesting that it is a shared feature of cystic renal diseases and independent of genotypic variation [22,23] . Our study demonstrated that in the LPK rat, NF-κB proteins are expressed in early disease and are constitutively present throughout life.…”

mentioning

confidence: 76%

“…In the past decade, in vivo studies have demonstrated an upregulation of NF-κB proteins in PKD, but there has been limited information regarding the specific NF-κB proteins involved and their expression throughout disease progression [22,23] . The first main finding of this study is that a diverse array of NF-κB proteins, including p50, P-p105, p65, RelB and c-rel, is present in LPK kidneys.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the complexity of the NF-κB system, the previous studies of NF-κB in PKD mainly or solely focused on p65, and in some cases did not specify the Ta MHT et al . Expression of NF-κB in PKD particular NF-κB subunits that were investigated [22,23] . Therefore, the first aim of the current study was to examine the expression and localization of a spectrum of NF-κB proteins, in a chronic disease model of PKD and in human cystic renal disease.…”

Section: Introductionmentioning

confidence: 99%

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Constitutive renal Rel/nuclear factor-κB expression in Lewis polycystic kidney disease rats

Schwensen

Liuwantara

et al. 2016

WJN

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Author contributions: Schwensen KG conducted the animal study, performed sample collection and histological staining; Ta MHT performed the immunofluorescence, Western blotting, and qPCR experiments, analyzed data and drafted the manuscript; Huso DL and Watnick T developed the Pkd2 knockout mouse model and provided paraffin embedded sections that were utilized for staining; Liuwantara D assisted with data interpretation and provided technical guidance with experimental methods; Rangan GK conceived of the study, conducted the animal study, performed sample collection and histological staining and reviewed and edited the manuscript; all authors read and approved of the final manuscript. Supported by Basic Study(LPK, a genetic ortholog of human nephronopthsis-9) from postnatal weeks 3 to 20. At each timepoint, renal disease progression and the mRNA expression of NF-κB-dependent genes (TNFa and CCL2) were determined. NF-κB was also histologically assessed in human PKD tissue. RESULTS:Progressive kidney enlargement in LPK rats was accompanied by increased renal cell proliferation and interstitial monocyte accumulation (peaking at weeks 3 and 10 respectively), and progressive interstitial fibrosis (with a smooth muscle actin and Sirius Red deposition significantly increased compared to Lewis kidneys from weeks 3 to 6 onwards). Rel/NF-κB proteins (phosphorylated-p105, p65, p50, c-Rel and RelB) were expressed in cystic epithelial cells (CECs) of LPK kidneys as early as postnatal week 3 and sustained until latestage disease at week 20. From weeks 10 to 20, nuclear p65, p50, RelB and cytoplasmic IκBa protein levels, and TNFa and CCL2 expression, were upregulated in LPK compared to Lewis kidneys. NF-κB proteins were consistently expressed in CECs of human PKD. The DNA damage marker γ-H2AX was also identified in the CECs of LPK and human polycystic kidneys. CONCLUSION:Several NF-κB proteins are consistently expressed in CECs in human and experimental PKD. These data suggest that the upregulation of both the canonical and non-canonical pathways of NF-κB signaling may be a constitutive and early pathological feature of cystic renal diseases. Core tip: Until now, there has been limited information regarding the specific nuclear factor (NF)-κB proteins involved in polycystic kidney disease (PKD) and their expression throughout disease progression. Our study demonstrated that a diverse array of NF-κB proteins is expressed in the renal cyst-lining cells of a chronic rodent model of PKD, and that NF-κB expression is constitutive over time. NF-κB was also identified in human PKD, suggesting that NF-κB upregulation is common to renal cystic disease models. Our data suggest that components of both the canonical and non-canonical NF-κB pathway are upregulated in PKD. Future studies should be directed at verifying whether specific NF-κB inhibition can attenuate interstitial inflammation and cyst growth, and slow the decline in renal function in in vivo models of PKD.Ta MHT, Schwensen KG, Liuwantara D, Huso DL, Watnick T, Rangan GK. Con...

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Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 73%

mentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Constitutive renal Rel/nuclear factor-κB expression in Lewis polycystic kidney disease rats

Schwensen

Liuwantara

et al. 2016

WJN

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cAMP‐Induced Nuclear Condensation of CRTC2 Promotes Transcription Elongation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease

Song

Wang

et al. 2022

Advanced Science

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Formation of biomolecular condensates by phase separation has recently emerged as a new principle for regulating gene expression in response to extracellular signaling. However, the molecular mechanisms underlying the coupling of signal transduction and gene activation through condensate formation, and how dysregulation of these mechanisms contributes to disease progression, remain elusive. Here, the authors report that CREB-regulated transcription coactivator 2 (CRTC2) translocates to the nucleus and forms phase-separated condensates upon activation of cAMP signaling. They show that intranuclear CRTC2 interacts with positive transcription elongation factor b (P-TEFb) and activates P-TEFb by disrupting the inhibitory 7SK snRNP complex. Aberrantly elevated cAMP signaling plays central roles in the development of autosomal dominant polycystic kidney disease (ADPKD). They find that CRTC2 localizes to the nucleus and forms condensates in cystic epithelial cells of both mouse and human ADPKD kidneys. Genetic depletion of CRTC2 suppresses cyst growth in an orthologous ADPKD mouse model. Using integrative transcriptomic and cistromic analyses, they identify CRTC2-regulated cystogenesis-associated genes, whose activation depends on CRTC2 condensate-facilitated P-TEFb recruitment and the release of paused RNA polymerase II. Together, their findings elucidate a mechanism by which CRTC2 nuclear condensation conveys cAMP signaling to transcription elongation activation and thereby promotes cystogenesis in ADPKD.

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Developmental signaling: Does it bridge the gap between cilia dysfunction and renal cystogenesis?

Tran

Sharma

et al. 2014

Birth Defects Research Pt C

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For more than a decade, evidence has accumulated linking dysfunction of primary cilia to renal cystogenesis, yet molecular mechanisms remain undefined. The pathogenesis of renal cysts is complex, involving multiple cellular aberrations and signaling pathways. Adding to this complexity, primary cilia exhibit multiple roles in a context-dependent manner. On renal epithelial cells, primary cilia act as mechanosensors and trigger extracellular Ca2+ influx in response to laminar fluid flow. During mammalian development, primary cilia mediate the Hedgehog (Hh), Wnt, and Notch pathways, which control cell proliferation and differentiation, and tissue morphogenesis. Further, experimental evidence suggests the developmental state of the kidney strongly influences renal cystic disease. Thus, we review evidence for regulation of Ca2+ and cAMP, key molecules in renal cystogenesis, at the primary cilium, the role of Hh, Wnt, and Notch signaling in renal cystic disease, and the interplay between these developmental pathways and Ca2+ signaling. Indeed if these developmental pathways influence renal cystogenesis, these may represent novel therapeutic targets that can be integrated into a combination therapy for renal cystic disease.

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c-Met and NF-κB–Dependent Overexpression of Wnt7a and -7b and Pax2 Promotes Cystogenesis in Polycystic Kidney Disease

Cited by 58 publications

References 66 publications

Constitutive renal Rel/nuclear factor-κB expression in Lewis polycystic kidney disease rats

Constitutive renal Rel/nuclear factor-κB expression in Lewis polycystic kidney disease rats

cAMP‐Induced Nuclear Condensation of CRTC2 Promotes Transcription Elongation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease

Developmental signaling: Does it bridge the gap between cilia dysfunction and renal cystogenesis?

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