Casein kinase 1 ε and 1α as novel players in polycystic kidney disease and mechanistic targets for (R)-roscovitine and (S)-CR8.

Casein kinase 1ε and 1α as novel players in polycystic kidney disease and mechanistic targets for (R)-roscovitine and (S)-CR8. Am J Physiol Renal Physiol. 2018 Mar 14;: Authors: Billot K, Coquil C, Villiers B, Josselin-Foll B, Desban N, Delehouze C, Oumata N, Le Meur Y, Boletta A, Weimbs T, Grosch M, Witzgall R, Saunier S, Fischer E, Pontoglio M, Fautrel A, Mrug M, Wallace DP, Tran PV, Trudel M, Bukanov NO, Ibraghimov-Beskrovnaya O, Meijer L Abstract Following the discovery of (R)-roscovitine's beneficial effects in three polycystic kidney disease (PKD) mouse models, cyclin-dependent kinases (CDKs) inhibitors are investigated as potential treatments. We have used various affinity chromatography approaches to identify the molecular targets of roscovitine and its more potent analogue (S)-CR8 in human and murine polycystic kidneys. These methods revealed casein kinases 1 (CK1) as additional targets of the two drugs. CK1ε expression at the mRNA and protein levels is enhanced in polycystic kidneys of 11 different PKD mouse models, as well as in human polycystic kidneys. A shift in the pattern of CK1α isoforms is observed in all PKD mouse models. Further, the catalytic activities of both CK1ε and CK1α are increased in mouse polycystic kidneys. Inhibition of CK1ε and CK1α may thus contribute to the long-lasting attenuating effects of roscovitine and (S)-CR8 on cyst development. CDKs and CK1s may constitute...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research

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Source: eLife - Category: Biomedical Science Tags: Developmental Biology Human Biology and Medicine Source Type: research
Emerging evidence has demonstrated that epigenetic regulation plays a vital role in gene expression under normal and pathological conditions. Alterations in the expression and activation of histone methyltransferases (HMTs) have been reported in preclinical models of multiple kidney diseases, including acute kidney injury, chronic kidney disease, diabetic nephropathy, polycystic kidney disease, and renal cell carcinoma. Pharmacological inhibition of these enzymes has shown promise in preclinical models of those renal diseases. In this review, we summarize recent knowledge regarding expression and activation of various HMTs...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
Contributors : Jin He ; Zhe ZhangSeries Type : Expression profiling by high throughput sequencingOrganism : Sus scrofaBased on the dosage effect hypothesis, renal cysts could arise in transgenic murine models overexpressing either PKD1 or PKD2, which are causal genes responsible for autosomal dominant polycystic kidney disease (ADPKD). To prove whether PKD genes overexpression is a universal mechanism driving cystogenesis or is merely restricted to rodents, other animal models are required. Previously, we failed to observe any renal cysts in a PKD2 overexpression transgenic pig model partially due to epigenetic silencing o...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Sus scrofa Source Type: research
AbstractA 14-year-old Japanese boy was diagnosed with immunoglobulin A nephropathy resulting in end-stage kidney disease (ESKD). He underwent ABO-compatible living kidney transplantation from his father at the age of 27. In the process of selecting a donor before the transplantation, it turned out that his mother had polycystic kidneys and that her family had a history of hypertension and cerebrovascular diseases. The patient himself also had bilateral multiple kidney cysts, with a normal-sized kidney, confusing us to make the diagnosis of acquired cystic kidney disease (ACKD) or ADPKD difficult at that point. Seventeen ye...
Source: CEN Case Reports - Category: Urology & Nephrology Source Type: research
CONCLUSIONS: Tolvaptan have a beneficial effect on ADPKD, but associated with an increase of adverse events on high dose when comparing with the placebo. Further RCTs studies on tolvaptan may be required to support this conclusion. PMID: 31793415 [PubMed - as supplied by publisher]
Source: Combinatorial Chemistry and High Throughput Screening - Category: Chemistry Authors: Tags: Comb Chem High Throughput Screen Source Type: research
CONCLUSIONS: The point prevalence of definite and likely ADPKD observed in this study is higher than those reported in the literature, but lower than genetic prevalence based on estimates of disease expectancy or on analysis of large population-sequencing databases. PMID: 31791998 [PubMed - as supplied by publisher]
Source: Clinical Journal of the American Society of Nephrology : CJASN - Category: Urology & Nephrology Authors: Tags: Clin J Am Soc Nephrol Source Type: research
Abstract Polycystin 2 (PC2) is one of two main protein types responsible for the underlying etiology of autosomal dominant polycystic kidney disease (ADPKD), the most prevalent monogenic renal disease in the world. This debilitating and currently incurable condition is caused by loss-of-function mutations in PKD2 and PKD1, the genes encoding for PC2 and Polycystin 1 (PC1), respectively. Two-hit mutation events in these genes lead to renal cyst formation and eventual kidney failure, the main hallmarks of ADPKD. Though much is known concerning the physiological consequences and dysfunctional signaling mechanisms res...
Source: Cellular Signalling - Category: Cytology Authors: Tags: Cell Signal Source Type: research
Contributors : Aniruddha Chatterjee ; Sarah Bowden ; Micheal Eccles ; Michael Bates ; Euan Rodger ; Cherie StaynerSeries Type : Methylation profiling by high throughput sequencingOrganism : Homo sapiensLimited data exists on alterations in DNA methylation that are associated with Autosomal Dominant Polycystic Kidney Disease (ADPKD). Given there are similarities between cystic kidney disease and neoplasia, and that DNA methylation inhibitors are FDA-approved for the treatment of myelodysplastic syndrome, we performed genome-scale methylation analysis of cortical kidney tissue from four ADPKD patients and nonADPKD cortical k...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Methylation profiling by high throughput sequencing Homo sapiens Source Type: research
Publication date: Available online 29 November 2019Source: Stem Cell ResearchAuthor(s): Piera Trionfini, Osele Ciampi, Elena Romano, Ariela Benigni, Susanna TomasoniAbstractAutosomal dominant polycystic kidney disease (ADPKD) is the most prevalent inherited renal disease, characterized by multiple cysts that can lead to kidney failure resulting in end-stage renal disease. ADPKD is mainly caused by mutations in either the PKD1 and PKD2 genes, encoding for polycystin-1 and polycystin-2, respectively. In order to clarify the disease mechanisms, here we describe the generation of two isogenic induced pluripotent stem cell (iPS...
Source: Stem Cell Research - Category: Stem Cells Source Type: research
Purpose of review Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor which regulates a wider range of downstream pathways than previously thought. This review focuses on the novel findings about the internal regulatory mechanisms of Nrf2, the expanding understanding of its role in maintaining cellular homeostasis and the attempts to broaden the clinical application of its activators. Recent findings Nrf2 is in charge of the maintenance of cellular homeostasis under stress and there exist the internal regulatory mechanisms for Nrf2 which have recently been elucidated. New downstream pathways o...
Source: Current Opinion in Nephrology and Hypertension - Category: Urology & Nephrology Tags: HORMONES, AUTACOIDS, NEUROTRANSMITTERS AND GROWTH FACTORS: Edited by Mark Cooper and Merlin Thomas Source Type: research
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