c-Jun N-terminal kinase (JNK) signaling contributes to cystic burden in polycystic kidney disease

Smith, Abigail O.; Jonassen, Julie A.; Preval, Kenley M; Davis, Roger J.; Pazour, Gregory J.

doi:10.1371/journal.pgen.1009711

Cited by 12 publications

(10 citation statements)

References 86 publications

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“…Our results suggest no synergetic effect of the two stresses as the addition of febrile-mimicking heat stress does not change the length of the ciliated cell but dramatically decreases the frequency of ciliated cells. Current work also extends the previous observation regarding the potential role of MAPK kinase JNK in ciliogenesis 18,19,21 , adding the context of the inflammatory response, a previously unreported role for JNK kinase. Generally, p38MAPK and JNK are activated by the MAP kinase kinase kinases (MKKKs or MAP3Ks; such as Mixed Lineage Kinases (MLKs).…”

Section: Resultssupporting

confidence: 85%

“…TNFalpha activates multiple downstream MLK targets, with p38 and JNK being among the best-characterized downstream stress kinases 17 . Moreover, JNK is involved in the ciliarelated genetic kidney polycystic disorder 18,19 and ciliogenesis in multiciliated pulmonary cells 21 , and both p38 and JNK were reported to affect atypical centrosome maturation during immune response in non-ciliated macrophages and RPE cells 7,22 . To evaluate the role of JNK and p38 on TNF-induced cilia elongation and frequency, we used a wellcharacterized small molecule JNK inhibitor SP-600125 and p38 inhibitor BIRB796 (Figure 3).…”

Section: Tnf-alpha Induces Cilia Elongation Via Mlk Signalingmentioning

confidence: 99%

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TNF-alpha promotes cilia elongation via Mixed Lineage Kinases signaling

Kumari,

Caliz,

Kant

et al. 2023

Preprint

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The primary cilium is characteristic of most of non-immune cells and acts as an environmental signal transduction sensor. The defects in primary cilium have profound consequences on the developmental program, including the maturation of retinal epithelium. The ciliary length is tightly regulated during ciliogenesis. Additionally, many features of ciliogenesis are shared with an immune synapse formation. While the interaction between the cells within an immune synapse is well-characterized, the impact of inflammatory stresses on ciliogenesis in non-immune cells remains elusive. The current study investigates the outcome of inflammatory stimuli for the primary cilium in human retinal epithelial cells. Here, we report that the exposure of retinal epithelium cells to pro-inflammatory cytokine TNF-alpha elongates cilia in a Mixed-Lineage Kinase (MLK) - dependent manner. In contrast, febrile condition-mimicking heat stress dramatically reduced the number of ciliated cells regardless of TNF-alpha exposure, suggesting distinct but rapid effects of inflammatory stresses on ciliogenesis.

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Section: Resultssupporting

confidence: 85%

Section: Tnf-alpha Induces Cilia Elongation Via Mlk Signalingmentioning

confidence: 99%

TNF-alpha promotes cilia elongation via Mixed Lineage Kinases signaling

Kumari,

Caliz,

Kant

et al. 2023

Preprint

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“…To validate the epithelial expression of Tacstd2 predicted by single-cell RNAseq, we immuno-stained kidney tissues collected from the same cohort of animals that were used for RNA isolation in this study (Fig 4A, 4B). In addition, to see how Tacstd2 responds in more highly cystic kidneys, we examined P21 tissue collected from another study where Pkd2 was deleted in the early post-natal period by tamoxifen treatment of mothers nursing Rosa26-Cre ERT2 , Pkd2 flox/flox pups (20) (Fig 4A, 4B). We find that Tacstd2 does not stain proximal tubules in either control or Pkd2 mutant tissue but does label collecting ducts in both control and experimental kidneys (Fig 4C).…”

Section: Resultsmentioning

confidence: 99%

The Tumor-Associated Calcium Signal Transducer 2 (TACSTD2) oncogene is upregulated in pre-cystic epithelial cells revealing a new target for polycystic kidney disease

Smith,

Frantz,

Preval

et al. 2023

Preprint

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Polycystic kidney disease (PKD) is an important cause of end stage renal disease, but treatment options are limited. While later stages of the disease have been extensively studied, mechanisms driving the initial conversion of renal tubules into cysts are not understood. To identify factors that promote the initiation of cysts we deleted polycystin-2 (Pkd2) in mice and surveyed transcriptional changes before and immediately after cysts developed. We identified 74 genes which we term cyst initiation candidates (CICs). To identify conserved changes with relevance to human disease we compared these murine CICs to single cell transcriptomic data derived from patients with PKD and from healthy controls. Tumor-associated calcium signal transducer 2 (Tacstd2) stood out as an epithelial-expressed gene whose levels were elevated prior to cystic transformation and further increased with disease progression. Human tissue biopsies and organoids show that TACSTD2 protein is low in normal kidney cells but is elevated in cyst lining cells. While TACSTD2 has not been studied in PKD, it has been studied in cancer where it is highly expressed in solid tumors while showing minimal expression in normal tissue. This property is being exploited by antibody drug conjugates that target TACSTD2 for the delivery of cytotoxic drugs. Our finding that Tacstd2 is highly expressed in cysts, but not normal tissue, suggests that it should be explored as a candidate for drug development in PKD. More immediately, our work suggests that PKD patients undergoing TACSTD2 treatment for cancer should be monitored for kidney effects.One Sentence SummaryThe oncogene, tumor-associated calcium signal transducer 2 (Tacstd2) mRNA increased in abundance shortly after Pkd2 loss and may be a driver of cyst initiation in polycystic kidney disease.

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“…JNK phosphorylates c-jun to activate the AP-1 transcription factor which is known to play a major role in the regulation of inflammatory genes in both skin and renal fibrosis [ 75 – 77 ]. Active JNK is elevated in diseased kidneys and early clinical trials as well as preclinical models suggest that JNK inhibitors may have some efficacy in treating fibrotic kidney disease [ 78 , 79 ]. Active JNK is also seen in keloids and hypertrophic scars of the skin where it has been proposed as a therapeutic target [ 80 , 81 ].…”

Section: Discussionmentioning

confidence: 99%

Induction of pro-inflammatory genes by fibronectin DAMPs in three fibroblast cell lines: Role of TAK1 and MAP kinases

2023

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Changes in the organization and structure of the fibronectin matrix are believed to contribute to dysregulated wound healing and subsequent tissue inflammation and tissue fibrosis. These changes include an increase in the EDA isoform of fibronectin as well as the mechanical unfolding of fibronectin type III domains. In previous studies using embryonic foreskin fibroblasts, we have shown that fibronectin’s EDA domain (FnEDA) and the partially unfolded first Type III domain (FnIII-1c) function as Damage Associated Molecular Pattern (DAMP) molecules to stimulate the induction of inflammatory cytokines by serving as agonists for Toll-Like Receptor-4 (TLR4). However, the role of signaling molecules downstream of TLR-4 such as TGF-β Activated Kinase 1 (TAK1) and Mitogen activated protein kinases (MAPK) in regulating the expression of fibronectin DAMP induced inflammatory genes in specific cell types is not known. In the current study, we evaluate the molecular steps regulating the fibronectin driven induction of inflammatory genes in three human fibroblast cell lines: embryonic foreskin, adult dermal, and adult kidney. The fibronectin derived DAMPs each induce the phosphorylation and activation of TAK1 which results in the activation of two downstream signaling arms, IKK/NF-κB and MAPK. Using the specific inhibitor 5Z-(7)-Oxozeanol as well as siRNA, we show TAK1 to be a crucial signaling mediator in the release of cytokines in response to fibronectin DAMPs in all three cell types. Finally, we show that FnEDA and FnIII-1c induce several pro-inflammatory cytokines whose expression is dependent on both TAK1 and JNK MAPK and highlight cell-type specific differences in the gene-expression profiles of the fibroblast cell-lines.

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c-Jun N-terminal kinase (JNK) signaling contributes to cystic burden in polycystic kidney disease

Cited by 12 publications

References 86 publications

TNF-alpha promotes cilia elongation via Mixed Lineage Kinases signaling

TNF-alpha promotes cilia elongation via Mixed Lineage Kinases signaling

The Tumor-Associated Calcium Signal Transducer 2 (TACSTD2) oncogene is upregulated in pre-cystic epithelial cells revealing a new target for polycystic kidney disease

Induction of pro-inflammatory genes by fibronectin DAMPs in three fibroblast cell lines: Role of TAK1 and MAP kinases

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