Epithelial-to-mesenchymal transition in cyst lining epithelial cells in an orthologous PCK rat model of autosomal-recessive polycystic kidney disease

Togawa, Hiroko; Nakanishi, Koichi; Mukaiyama, Hironobu; Hama, Taketsugu; Shima, Yuko; Sako, Mayumi; Miyajima, Masayasu; Nozu, Kandai; Nishii, Kazuhiro; Nagao, Shizuko; Takahashi, Hisahide; Iijima, Kazumoto; Yoshikawa, Norishige

doi:10.1152/ajprenal.00038.2010

Cited by 44 publications

(34 citation statements)

References 46 publications

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“…1B). To assess whether this was possibly due to a restoration of cellular differentiation, we assayed the cell state by immunostaining for the mesenchymal markers vimentin and alpha smooth muscle actin (αSMA) and the epithelial marker cytokeratin, which have been shown to be aberrantly expressed in PKD (39,40). We found that kidney epithelial cells are in a de-differentiated state in jck mice, demonstrating increased expression of vimentin and αSMA in the interstitial tissue and cystic epithelial cells and decrease expression of cytokeratin (Fig.…”

Section: Resultsmentioning

confidence: 99%

Reduction of ciliary length through pharmacologic or genetic inhibition of CDK5 attenuates polycystic kidney disease in a model of nephronophthisis

Husson¹,

Moreno²,

Smith³

et al. 2016

Hum. Mol. Genet.

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Polycystic kidney diseases (PKDs) comprise a subgroup of ciliopathies characterized by the formation of fluid-filled kidney cysts and progression to end-stage renal disease. A mechanistic understanding of cystogenesis is crucial for the development of viable therapeutic options. Here, we identify CDK5, a kinase active in post mitotic cells, as a new and important mediator of PKD progression. We show that long-lasting attenuation of PKD in the juvenile cystic kidneys (jck) mouse model of nephronophthisis by pharmacological inhibition of CDK5 using either R-roscovitine or S-CR8 is accompanied by sustained shortening of cilia and a more normal epithelial phenotype, suggesting this treatment results in a reprogramming of cellular differentiation. Also, a knock down of Cdk5 in jck cells using small interfering RNA results in significant shortening of ciliary length, similar to what we observed with R-roscovitine. Finally, conditional inactivation of Cdk5 in the jck mice significantly attenuates cystic disease progression and is associated with shortening of ciliary length as well as restoration of cellular differentiation. Our results suggest that CDK5 may regulate ciliary length by affecting tubulin dynamics via its substrate collapsin response mediator protein 2. Taken together, our data support therapeutic approaches aimed at restoration of ciliogenesis and cellular differentiation as a promising strategy for the treatment of renal cystic diseases.

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Section: Resultsmentioning

confidence: 99%

Reduction of ciliary length through pharmacologic or genetic inhibition of CDK5 attenuates polycystic kidney disease in a model of nephronophthisis

Husson¹,

Moreno²,

Smith³

et al. 2016

Hum. Mol. Genet.

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“…103–107 Tubular expression of fibroblast markers such as αSMA, vimentin and FSP1 in fibrotic kidneys is well documented. 8,103,105,106,108 Key mediators of EMT-regulatory signaling such as TGF-β1/Smad, ILK, Wnt/β-catenin and Snail1 are preferentially activated in renal tubular epithelia after injury. 109,110 Furthermore, morphological evidence indicates that epithelial cells do indeed traverse the tubular basement membrane (TBM) into the interstitium after injury.…”

Section: Activationmentioning

confidence: 99%

Cellular and molecular mechanisms of renal fibrosis

2011

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Renal fibrosis, particularly tubulointerstitial fibrosis, is the common final outcome of almost all progressive chronic kidney diseases. Renal fibrosis is also a reliable predictor of prognosis and a major determinant of renal insufficiency. Irrespective of the initial causes, renal fibrogenesis is a dynamic and converging process that consists of four overlapping phases: priming, activation, execution and progression. Nonresolving inflammation after a sustained injury sets up the fibrogenic stage (priming) and triggers the activation and expansion of matrix-producing cells from multiple sources through diverse mechanisms, including activation of interstitial fibroblasts and pericytes, phenotypic conversion of tubular epithelial and endothelial cells and recruitment of circulating fibrocytes. Upon activation, matrix-producing cells assemble a multicomponent, integrin-associated protein complex that integrates input from various fibrogenic signals and orchestrates the production of matrix components and their extracellular assembly. Multiple cellular and molecular events, such as tubular atrophy, microvascular rarefaction and tissue hypoxia, promote scar formation and ensure a vicious progression to end-stage kidney failure. This Review outlines our current understanding of the cellular and molecular mechanisms of renal fibrosis, which could offer novel insights into the development of new therapeutic strategies.

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“…In ADPKD, E-cadherin, along with other proteins that regulate cell polarity, is trapped cytoplasmically, potentially due to a failure of recruitment by polycystin-1 [152, 153]. EMT-associated proteins including smooth muscle actin and Snail are downregulated in cystic tissue [154, 155], as in cancer cells that have undergone EMT. Typically, cancer cells that have become mesenchymal are more migratory.…”

Section: Adpkd and The Hallmarks Of Cancermentioning

confidence: 99%

“…Similarities in sub-processes associated with invasion: disrupted PCP [139–145], mitotic spindle misorientation [140, 141, 147–150], deregulation of EMT markers/drivers (TGF-β, E-cadherin) [41, 152–155]…”

Section: Figurementioning

confidence: 99%

The hallmarks of cancer: relevance to the pathogenesis of polycystic kidney disease

et al. 2015

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Autosomal dominant polycystic kidney disease (ADPKD) is a progressive inherited disorder in which renal tissue is gradually replaced with fluid-filled cysts, giving rise to chronic kidney disease (CKD) and progressive loss of renal function. ADPKD is also associated with liver ductal cysts, hypertension, chronic pain and extrarenal problems such as cerebral aneurysms. Intriguingly, improved understanding of the signalling and pathological derangements characteristic of ADPKD has revealed marked similarities to those of solid tumours, even though the gross presentation of tumours and the greater morbidity and mortality associated with tumour invasion and metastasis would initially suggest an entirely different disease processes. The commonalities between ADPKD and cancer are provocative, particularly in the context of recent preclinical and clinical studies of ADPKD that have shown promise with drugs that were originally developed for cancer. The potential therapeutic benefit of such repurposing has led us to review in detail the pathological features of ADPKD through the lens of the defined, classic hallmarks of cancer. In addition, we have evaluated features typical of ADPKD, and determined whether evidence supports the presence of such features in cancer cells. This analysis, which places pathological processes in the context of defined signalling pathways and approved signalling inhibitors, highlights potential avenues for further research and therapeutic exploitation in both diseases.

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Epithelial-to-mesenchymal transition in cyst lining epithelial cells in an orthologous PCK rat model of autosomal-recessive polycystic kidney disease

Abstract: N. Epithelial-to-mesenchymal transition in cyst lining epithelial cells in an orthologous PCK rat model of autosomal-recessive polycystic kidney disease.

Cited by 44 publications

References 46 publications

Reduction of ciliary length through pharmacologic or genetic inhibition of CDK5 attenuates polycystic kidney disease in a model of nephronophthisis

Reduction of ciliary length through pharmacologic or genetic inhibition of CDK5 attenuates polycystic kidney disease in a model of nephronophthisis

Cellular and molecular mechanisms of renal fibrosis

The hallmarks of cancer: relevance to the pathogenesis of polycystic kidney disease

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