CDK inhibitors R-roscovitine and S-CR8 effectively block renal and hepatic cystogenesis in an orthologous model of ADPKD

Bukanov, Nikolay O.; Moreno, Sarah; Natoli, Thomas A.; Rogers, Kelly A.; Smith, Laurie; Ledbetter, Steven; Oumata, Nassima; Galons, Hervé; Meijer, Laurent; Ibraghimov‐Beskrovnaya, Oxana

doi:10.4161/cc.22375

Cited by 56 publications

(46 citation statements)

References 49 publications

(57 reference statements)

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“…We have obtained functional insight into the NPHP-RC pathogenesis and investigated the effect of CDK1/2i on loss of function of CEP290. Use of CDKi as a potential treatment strategy has already shown some success in vivo (25,26), and our data confirm that changes in CDK protein levels may be widespread in patients with NPHP, justifying this approach. We would like to extend this knowledge to other forms of chronic kidney disease (27) and renal fibrosis, which are associated with DNA damage signaling.…”

Section: B Levels Were Higher In Cep290supporting

confidence: 64%

DNA replication stress underlies renal phenotypes in CEP290-associated Joubert syndrome

Slaats

Saldivar

Bacal

et al. 2015

Journal of Clinical Investigation

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Section: B Levels Were Higher In Cep290supporting

confidence: 64%

DNA replication stress underlies renal phenotypes in CEP290-associated Joubert syndrome

Slaats

Saldivar

Bacal

et al. 2015

Journal of Clinical Investigation

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“…The majority of PKD studies using 3D tissue culture have used MDCK cells as the cell line of choice (6)(7)(8)(9)(10)(11)(12), but PC2-dependent Ca 2+ signaling has not been studied extensively in this cell line. Here, we demonstrate another cell line, LLC-PK1, in which much is known about PC2-dependent Ca 2+ signaling, also has the capacity to support cysts when PC2 or InsP3R expression levels are decreased and when cultured in hormone-containing media.…”

Section: Discussionmentioning

confidence: 99%

“…21). Recently, 3D tissues have been developed that incorporate mouse cells containing a shRNA-mediated knockdown of PC1 (9,19). The benefits of this system include the use of a cell line, thus eliminating the need to isolate primary cells, and the use of cells with a stable genetic background.…”

mentioning

confidence: 99%

“…Advances in 3D tissue culture over the past 2 decades have improved the ability to model cyst development in vitro. However, previously published 3D tissue models of ADPKD have relied upon shortterm culture of Madin-Darby canine kidney (MDCK) cells (6)(7)(8)(9)(10)(11)(12) or cells from patients (13)(14)(15)(16)(17)(18) or PC1-null mice (19,20; for review, see ref. 21).…”

mentioning

confidence: 99%

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Cyst formation following disruption of intracellular calcium signaling

Kuo¹,

DesRochers

Kimmerling

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in polycystin 1 and 2 (PC1 and PC2) cause the common genetic kidney disorder autosomal dominant polycystic kidney disease (ADPKD). It is unknown how these mutations result in renal cysts, but dysregulation of calcium (Ca 2+ ) signaling is a known consequence of PC2 mutations. PC2 functions as a Ca 2+ -activated Ca 2+ channel of the endoplasmic reticulum. We hypothesize that Ca 2+ signaling through PC2, or other intracellular Ca 2+ channels such as the inositol 1,4,5-trisphosphate receptor (InsP3R), is necessary to maintain renal epithelial cell function and that disruption of the Ca 2+ signaling leads to renal cyst development. The cell line LLC-PK1 has traditionally been used for studying PKD-causing mutations and Ca 2+ signaling in 2D culture systems. We demonstrate that this cell line can be used in long-term (8 wk) 3D tissue culture systems. In 2D systems, knockdown of InsP3R results in decreased Ca 2+ transient signals that are rescued by overexpression of PC2. In 3D systems, knockdown of either PC2 or InsP3R leads to cyst formation, but knockdown of InsP3R type 1 (InsP3R1) generated the largest cysts. InsP3R1 and InsP3R3 are differentially localized in both mouse and human kidney, suggesting that regional disruption of Ca 2+ signaling contributes to cystogenesis. All cysts had intact cilia 2 wk after starting 3D culture, but the cells with InsP3R1 knockdown lost cilia as the cysts grew. Studies combining 2D and 3D cell culture systems will assist in understanding how mutations in PC2 that confer altered Ca 2+ signaling lead to ADPKD cysts. primary cilia | polycysin 2 | calcium release T he commonly occurring genetic kidney disorder, autosomal dominant polycystic kidney disease (ADPKD), is the result of mutations in polycystin 1 or 2 (PC1 or PC2). The progressive cyst formation within all segments of the nephron that defines the disorder leads to renal failure requiring treatment by dialysis and/or organ transplantation (1-3). Altered Ca 2+ signaling is one of several pathways that have been implicated in the disease (4, 5). A major limitation toward elucidating the role of Ca 2+ signaling in cyst formation has been the lack of easily manipulated, physiologically relevant experimental methodologies.In the past, ADPKD research has relied largely upon data from mouse models and cells maintained in 2D cell culture. Mouse models have played a significant role in understanding the biology of cyst formation but are unable to fully recapitulate the physiology of disease progression in humans due to the inherent differences between the species including life span, genetics, and environment. Two-dimensional cell culture has the ability to provide information on signaling pathways and response to therapies in a fast, high-throughput manner, but is incapable of replicating the inherent 3D nature of cyst formation. Advances in 3D tissue culture over the past 2 decades have improved the ability to model cyst development in vitro. However, previously published 3D tissue models of ADPKD have relied upon shortter...

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“…This mechanism can be targeted by drugs, as has been shown in models of renal cystic disease using roscovitine and other drugs that interfere with cell cycle regulation. 73 …”

Section: Future Directionsmentioning

confidence: 99%

The Future of Polycystic Kidney Disease Research—As Seen By the 12 Kaplan Awardees

Antignac

Calvet

Germino

et al. 2015

Journal of the American Society of Nephrology

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Polycystic kidney disease (PKD) is one of the most common life-threatening genetic diseases. Jared J. Grantham, M.D., has done more than any other individual to promote PKD research around the world. However, despite decades of investigation there is still no approved therapy for PKD in the United States. In May 2014, the University of Kansas Medical Center hosted a symposium in Kansas City honoring the occasion of Dr. Grantham's retirement and invited all the awardees of the Lillian Jean Kaplan International Prize for Advancement in the Understanding of Polycystic Kidney Disease to participate in a forward-thinking and interactive forum focused on future directions and innovations in PKD research. This article summarizes the contributions of the 12 Kaplan awardees and their vision for the future of PKD research.

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CDK inhibitors R-roscovitine and S-CR8 effectively block renal and hepatic cystogenesis in an orthologous model of ADPKD

Cited by 56 publications

References 49 publications

DNA replication stress underlies renal phenotypes in CEP290-associated Joubert syndrome

DNA replication stress underlies renal phenotypes in CEP290-associated Joubert syndrome

Cyst formation following disruption of intracellular calcium signaling

The Future of Polycystic Kidney Disease Research—As Seen By the 12 Kaplan Awardees

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