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https://www.readbyqxmd.com/read/28644734/high-throughput-phenotypic-screening-of-kinase-inhibitors-to-identify-drug-targets-for-polycystic-kidney-disease
#1
Tijmen H Booij, Hester Bange, Wouter N Leonhard, Kuan Yan, Michiel Fokkelman, Steven J Kunnen, Johannes G Dauwerse, Yu Qin, Bob van de Water, Gerard J P van Westen, Dorien J M Peters, Leo S Price
Polycystic kidney disease (PKD) is a prevalent disorder characterized by renal cysts that lead to kidney failure. Various signaling pathways have been targeted to stop disease progression, but most interventions still focus on alleviating PKD-associated symptoms. The mechanistic complexity of the disease, as well as the lack of functional in vitro assays for compound testing, has made drug discovery for PKD challenging. To identify modulators of PKD, Pkd1(-/-) kidney tubule epithelial cells were applied to a scalable and automated 3D cyst culture model for compound screening, followed by phenotypic profiling to determine compound efficacy...
June 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28640449/polycystic-kidney-disease
#2
Joseph Ghata, Benjamin D Cowley
Renal cysts, which arise from renal tubules, can be seen in a variety of hereditary and nonhereditary entities. Common mechanisms associated with renal cyst formation include increased cell proliferation, epithelial fluid secretion, and extracellular matrix remodeling. Hereditary polycystic kidney disease (PKD) is seen as a component of numerous diseases. Autosomal dominant (AD) PKD is the most common potentially fatal hereditary disease in humans, causes renal failure in approximately 50% of affected individuals, and accounts for approximately 5% of end stage renal disease cases in the United States...
June 18, 2017: Comprehensive Physiology
https://www.readbyqxmd.com/read/28620080/the-sorting-nexin-3-retromer-pathway-regulates-the-cell-surface-localization-and-activity-of-a-wnt-activated-polycystin-channel-complex
#3
Shuang Feng, Andrew J Streets, Vasyl Nesin, Uyen Tran, Hongguang Nie, Marta Onopiuk, Oliver Wessely, Leonidas Tsiokas, Albert C M Ong
Autosomal dominant polycystic kidney disease (ADPKD) is caused by inactivating mutations in PKD1 (85%) or PKD2 (15%). The ADPKD proteins encoded by these genes, polycystin-1 (PC1) and polycystin-2 (PC2), form a plasma membrane receptor-ion channel complex. However, the mechanisms controlling the subcellular localization of PC1 and PC2 are poorly understood. Here, we investigated the involvement of the retromer complex, an ancient protein module initially discovered in yeast that regulates the retrieval, sorting, and retrograde transport of membrane receptors...
June 15, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28615245/the-regulatory-1%C3%AE-subunit-of-protein-kinase-a-modulates-renal-cystogenesis
#4
Hong Ye, Xiaofang Wang, Megan M Constans, Caroline R Sussman, Fouad Chebib, Maria V Irazabal, William F Young, Peter C Harris, Lawrence S Kirschner, Vicente E Torres
The failure of the polycystins (PCs) to function in primary cilia is thought to be responsible for Autosomal Dominant Polycystic Kidney Disease (ADPKD). Primary cilia integrate multiple cellular signaling pathways, including calcium, cAMP, Wnt, and Hedgehog, which control cell proliferation and differentiation. It has been proposed that mutated PCs result in reduced intracellular calcium, which in turn upregulates cAMP, protein kinase A (PKA) signaling, and subsequently other proliferative signaling pathways...
June 14, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28604956/-analysis-of-pkd1-gene-mutation-in-a-family-affected-with-autosomal-dominant-polycystic-kidney-disease
#5
Jin Mei, Min Wang, Hao Wang, Lidan Zhang, Pan Zhang
OBJECTIVE: To determine the molecular etiology for a family affected with autosomal dominant polycystic kidney disease and provide prenatal diagnosis for the family. METHODS: Clinical data of the family was collected. Target region sequencing with monogenetic disorders capture array combined with Sanger sequencing and bioinformatics analysis were performed in turn. SIFT and NCB1 were used to evaluate the conservation of the gene and pathogenicity of the identified mutation...
June 10, 2017: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
https://www.readbyqxmd.com/read/28604386/lysine-methyltransferase-smyd2-promotes-cyst-growth-in-autosomal-dominant-polycystic-kidney-disease
#6
Linda Xiaoyan Li, Lucy X Fan, Julie Xia Zhou, Jared J Grantham, James P Calvet, Julien Sage, Xiaogang Li
Autosomal dominant polycystic kidney disease (ADPKD) is driven by mutations in PKD1 and PKD2 genes. Recent work suggests that epigenetic modulation of gene expression and protein function may play a role in ADPKD pathogenesis. In this study, we identified SMYD2, a SET and MYND domain protein with lysine methyltransferase activity, as a regulator of renal cyst growth. SMYD2 was upregulated in renal epithelial cells and tissues from Pkd1-knockout mice as well as in ADPKD patients. SMYD2 deficiency delayed renal cyst growth in postnatal kidneys from Pkd1 mutant mice...
June 12, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28583565/role-of-urinary-neutrophil-gelatinase-associated-lipocalin-for-predicting-the-severity-of-renal-functions-in-patients-with-autosomal-dominant-polycystic-kidney-disease
#7
K Vareesangthip, K Vareesangthip, C Limwongse, K Reesukumal
BACKGROUND: Autosomal-dominant polycystic kidney disease (ADPKD) has a feature of disruption of tubular integrity with increased cellular proliferation and apoptosis. There are several known tubular membrane proteins in the pathogenesis of ADPKD, and one of these proteins is the neutrophil gelatinase-associated lipocalin (NGAL). NGAL is a protein expressed on renal tubular cells of which production is markedly increased in response to harmful stimuli such as ischemia or toxicity. OBJECTIVE: We aim to study whether urinary NGAL levels could be used as a marker to identify the severity of ADPKD in patients...
June 2017: Transplantation Proceedings
https://www.readbyqxmd.com/read/28578020/pathogenicity-analysis-of-novel-variations-in-chinese-han-patients-with-polycystic-kidney-disease
#8
Zishui Fang, Shiyan Xu, Yonghua Wang, Liwei Sun, Yi Feng, Yibin Guo, Hongyi Li, Weiying Jiang
OBJECTIVE: Locus and allellic heterogeneity in polycystic kidney disease (PKD) is a great challenge in precision diagnosis. We aim to establish comprehensive methods to distinguish the pathogenic mutations from the variations in PKD1, PKD2 and PKHD1 genes in a limited time and lay the foundation for precisely prenatal diagnosis, preimplantation genetic diagnosis and presymptom diagnosis of PKD. METHODS: Nested PCR combined with direct DNA sequencing were used to screen variations in PKD1, PKD2 and PKHD1 genes...
May 31, 2017: Gene
https://www.readbyqxmd.com/read/28560694/role-of-apoptosis-in-the-development-of-autosomal-dominant-polycystic-kidney-disease-adpkd
#9
REVIEW
Lukas Peintner, Christoph Borner
Autosomal dominant polycystic kidney disease (ADPKD) is a widespread genetic disorder in the Western world and is characterized by cystogenesis that often leads to end-stage renal disease (ESRD). Mutations in the pkd1 gene, encoding for polycystin-1 (PC1) and its interaction partner pkd2, encoding for polycystin-2 (PC2), are the main drivers of this disease. PC1 and PC2 form a multiprotein membrane complex at cilia sites of the plasma membrane and at intracellular membranes. This complex mediates calcium influx and stimulates various signaling pathways regulating cell survival, proliferation and differentiation...
July 2017: Cell and Tissue Research
https://www.readbyqxmd.com/read/28552828/down-regulation-of-polycystin-in-lymphatic-malformations-possible-role-in-the-proliferation-of-lymphatic-endothelial-cells
#10
Jian-Gang Ren, Hou-Fu Xia, Jie-Gang Yang, Jun-Yi Zhu, Wei Zhang, Gang Chen, Ji-Hong Zhao, Yan-Fang Sun, Yi-Fang Zhao
Lymphatic malformations (LMs) are composed of aberrant lymphatic vessels and regarded as benign growths of the lymphatic system. Recent studies have demonstrated that the mutant embryos of PKD1 and PKD2, encoding polycystin-1 (PC-1) and polycystin-2 (PC-2), respectively, result in aberrant lymphatic vessels similar to those observed in LMs. In this study, for the first time, we investigated PC-1 and PC-2 expression and assessed their roles in the development of LMs. Our results demonstrated that PC-1 and PC-2 gene and protein expression were obviously decreased in LMs compared with normal skin tissues...
May 25, 2017: Human Pathology
https://www.readbyqxmd.com/read/28549111/diabetic-db-db-mice-do-not-develop-heart-failure-upon-pressure-overload-a-longitudinal-in-vivo-pet-mri-and-mrs-study-on-cardiac-metabolic-structural-and-functional-adaptations
#11
Desiree Abdurrachim, Miranda Nabben, Verena Hoerr, Michael T Kuhlmann, Philipp Bovenkamp, Jolita Ciapaite, Ilvy M E Geraets, Will Coumans, Joost J F P Luiken, Jan F C Glatz, Michael Schäfers, Klaas Nicolay, Cornelius Faber, Sven Hermann, Jeanine J Prompers
Aim: Heart failure is associated with altered myocardial substrate metabolism and impaired cardiac energetics. Comorbidities like diabetes may influence the metabolic adaptations during heart failure development. We quantified to what extent changes in substrate preference, lipid accumulation, and energy status predict the longitudinal development of hypertrophy and failure in the non-diabetic and the diabetic heart. Methods and results: Transverse aortic constriction (TAC) was performed in non-diabetic ( db /+) and diabetic ( db/db ) mice to induce pressure overload...
May 26, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28545714/anticystogenic-activity-of-a-small-molecule-pak4-inhibitor-may-be-a-novel-treatment-for-autosomal-dominant-polycystic-kidney-disease
#12
Vicki J Hwang, Xia Zhou, Xiaonan Chen, Josephine Trott, Omran Abu Aboud, Kyuhwan Shim, Lai Kuan Dionne, Kenneth J Chmiel, William Senapedis, Erkan Baloglu, Moe R Mahjoub, Xiaogang Li, Robert H Weiss
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common hereditary renal disease with no currently available targeted therapies. Based on the established connection between β-catenin signaling and renal ciliopathies, and on data from our and other laboratories showing striking similarities of this disease and cancer, we evaluated the use of an orally bioavailable small molecule, KPT-9274 (a dual inhibitor of the protein kinase PAK4 and nicotinamide phosphoribosyl transferase), for treatment of ADPKD...
May 23, 2017: Kidney International
https://www.readbyqxmd.com/read/28526426/the-effects-of-troglitazone-on-ampk-in-hepg2-cells
#13
Katherine M Allen, Kimberly A Coughlan, Fabliha N Mahmood, Rudy J Valentine, Neil B Ruderman, Asish K Saha
AMP-activated protein kinase (AMPK) is an enzyme crucial in cellular metabolism found to be inhibited in many metabolic diseases including type 2 diabetes. Thiazolidinediones (TZDs) are a class of anti-diabetic drug known to activate AMPK through increased phosphorylation at Thr(172), however there has been no research to date on whether they have any effect on inhibition of AMPK's lesser known site of inhibition, Ser(485/491). HepG2 cells were treated with troglitazone and phosphorylation of AMPK was found to increase at both Thr(172) and Ser(485) in a dose- and time-dependent manner...
June 1, 2017: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28522688/polycystic-kidney-disease-without-an-apparent-family-history
#14
Ioan-Andrei Iliuta, Vinusha Kalatharan, Kairong Wang, Emilie Cornec-Le Gall, John Conklin, Marina Pourafkari, Ryan Ting, Chen Chen, Alessia C Borgo, Ning He, Xuewen Song, Christina M Heyer, Sarah R Senum, Young-Hwan Hwang, Andrew D Paterson, Peter C Harris, Korosh Khalili, York Pei
The absence of a positive family history (PFH) in 10%-25% of patients poses a diagnostic challenge for autosomal dominant polycystic kidney disease (ADPKD). In the Toronto Genetic Epidemiology Study of Polycystic Kidney Disease, 210 affected probands underwent renal function testing, abdominal imaging, and comprehensive PKD1 and PKD2 mutation screening. From this cohort, we reviewed all patients with and without an apparent family history, examined their parental medical records, and performed renal imaging in all available parents of unknown disease status...
May 18, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28522687/integrin-linked-kinase-signaling-promotes-cyst-growth-and-fibrosis-in-polycystic-kidney-disease
#15
Archana Raman, Gail A Reif, Yuqiao Dai, Aditi Khanna, Xiaogang Li, Lindsay Astleford, Stephen C Parnell, James P Calvet, Darren P Wallace
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by innumerous fluid-filled cysts and progressive deterioration of renal function. Previously, we showed that periostin, a matricellular protein involved in tissue repair, is markedly overexpressed by cyst epithelial cells. Periostin promotes cell proliferation, cyst growth, interstitial fibrosis, and the decline in renal function in PKD mice. Here, we investigated the regulation of these processes by the integrin-linked kinase (ILK), a scaffold protein that links the extracellular matrix to the actin cytoskeleton and is stimulated by periostin...
May 18, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28513986/pleiotropic-effects-of-chronic-phorbol-ester-treatment-to-improve-glucose-transport-in-insulin-resistant-cardiomyocytes
#16
Christelle Viglino, Bahareh Khoramdin, Guillaume Praplan, Christophe Montessuit
Stimulation of glucose transport is an important determinant of myocardial susceptibility to ischemia and reperfusion. Stimulation of glucose transport is markedly impaired in cardiomyocytes exposed to free fatty acids (FFA). Deactivation of the Focal Adhesion Kinase (FAK) by FFA contributes to glucose transport impairment, and could be corrected by chronic treatment with the phorbol ester TPA. However, TPA must have effects in addition to FAK reactivation to restore stimulated glucose transport. Chronic treatment with TPA improved basal and stimulated glucose transport in FFA-exposed, but not in control cardiomyocytes...
May 17, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28494735/perspectives-of-gene-therapies-in-autosomal-dominant-polycystic-kidney-disease
#17
Yuchen Xu, Ao Li, Guanqing Wu, Chaozhao Liang
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease in the clinic. The predominant clinical manifestation is bilateral and progressive cysts formation in the kidneys, impairs normal renal parenchyma, and ultimately leads to end-stage renal disease (ESRD). ADPKD is a heterogenic disease which is resulted from the mutations of PKD1 or PKD2 genes which encode polycystin-1 (PC1) and -2 (PC2), thereby multiple cell signaling pathways are involved. Although causative genes and aberrant signaling pathways have been investigated for decades, lack of effective and less side-effect treatment for the disease still perplex vast clinicians...
May 10, 2017: Current Gene Therapy
https://www.readbyqxmd.com/read/28468945/primary-cilia-control-the-maturation-of-tubular-lumen-in-renal-collecting-duct-epithelium
#18
Thomas Ernandez, Olga Komarynets, Alexandra Chassot, Soushma Sougoumarin, Priscilla Soulie, Yubao Wang, Roberto Montesano, Eric Feraille
The key role of the primary cilium in developmental processes is illustrated by ciliopathies resulting from genetic defects of its components. Ciliopathies include a large variety of dysmorphic syndromes that share in common the presence of multiple kidney cysts. These observations suggest that primary cilia may control morphogenetic processes in the developing kidney. In this study, we assessed the role of primary cilium in branching tubulogenesis and/or lumen development using kidney collecting duct-derived mCCDN21 cells that display spontaneous tubulogenic properties when grown in collagen/matrigel matrix...
May 3, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28461572/group-b-streptococci-induce-proinflammatory-responses-via-a-protein-kinase-d1-dependent-pathway
#19
Kirtikumar Upadhyay, Jeoung-Eun Park, Tae Won Yoon, Priyanka Halder, Young-In Kim, Victoria Metcalfe, Ajay J Talati, B Keith English, Ae-Kyung Yi
Group B streptococci (GBS) are one of the leading causes of life-threatening illness in neonates. Proinflammatory responses to GBS mediated through host innate immune receptors play a critical role in the disease manifestation. However, the mechanisms involved in proinflammatory responses against GBS, as well as the contribution of signaling modulators involved in host immune defense, have not been fully elucidated. In the present study, we investigated the role of protein kinase D (PKD)1 in the proinflammatory responses to GBS...
May 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28432464/insights-into-autosomal-dominant-polycystic-kidney-disease-by-quantitative-mass-spectrometry-based-proteomics
#20
REVIEW
Britta Diedrich, Jörn Dengjel
Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenetic disorder that is caused by mutations in the genes PKD1 and PKD2 encoding polycystin-1 and polycystin-2, respectively. Polycystin-1 and -2 form a complex, interact with several proteins involved in signal transduction and localize to discrete subcellular positions, most importantly the primary cilium. Whereas the causative mutations leading to ADPKD are known, the underlying deregulated cellular pathways are not well understood. In the current review, we introduce state-of-the-art mass spectrometry (MS)-based proteomic techniques and summarize their use in kidney and ADPKD research...
July 2017: Cell and Tissue Research
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