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Bo Zhang, Uyen Tran, Oliver Wessely
The development of the kidney relies on the establishment and maintenance of a precise tubular diameter of its functional units, the nephrons. This process is disrupted in Polycystic Kidney Disease (PKD) resulting in dilations of the nephron and renal cyst formation. In the course of exploring G-protein coupled signaling in the Xenopus pronephric kidney we discovered that loss of the G-protein alpha subunit Gnas results in a PKD phenotype. Polycystin-1, one of the genes mutated in human PKD, encodes for a protein resembling a G-protein coupled receptor...
March 12, 2018: Development
Dechao Xu, Yiyi Ma, Xiangchen Gu, Rongrong Bian, Yunhui Lu, Xiaohong Xing, Changlin Mei
BACKGROUND/AIMS: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder with mutations in PKD1 or PKD2. This study aimed to identify novel PKD1 and PKD2 mutations in Chinese patients with ADPKD. METHODS: Mutational analyses of both PKD genes were performed in 120 Chinese families with inherited ADPKD using long-range PCR and targeted next-generation sequencing approaches. Sanger sequencing was performed to check the positive mutations, while multiplex ligation-dependent probe amplification was adopted to examine those without mutations for the presence of large deletions...
March 6, 2018: Kidney & Blood Pressure Research
Rattikarn Noitem, Chaowalit Yuajit, Sunhapas Soodvilai, Chatchai Muanprasat, Varanuj Chatsudthipong
Overexpression of aquaporin 2 (AQP2) was observed and suggested to be involved in fluid secretion leading to cyst enlargement in polycystic kidney disease (PKD). The cyst expansion deteriorates the renal function and, therefore, therapies targeting cyst enlargement are of clinical interest. Of note, inhibition of vasopressin function using vasopressin 2 receptor (V2R) antagonist which decreased cAMP production along with AQP2 production and function can slow cyst growth in ADPKD. This finding supports the role of AQP2 in cyst enlargement...
March 7, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
T Fujimaru, T Mori, A Sekine, S Mandai, M Chiga, H Kikuchi, F Ando, Y Mori, N Nomura, S Iimori, S Naito, T Okado, T Rai, J Hoshino, Y Ubara, S Uchida, E Sohara
Distinguishing autosomal dominant polycystic kidney disease (ADPKD) from other inherited renal cystic diseases in patients with adult polycystic kidney disease and no family history is critical for correct treatment and appropriate genetic counseling. However, for patients with no family history, there are no definitive imaging findings that provide an unequivocal ADPKD diagnosis. We analyzed 53 adult polycystic kidney disease patients with no family history. Comprehensive genetic testing was performed using capture-based next-generation sequencing for 69 genes currently known to cause hereditary renal cystic diseases including ADPKD...
March 9, 2018: Clinical Genetics
Ao Li, Yuchen Xu, Song Fan, Jialin Meng, Xufeng Shen, Qian Xiao, Yuan Li, Li Zhang, Xiansheng Zhang, Guanqing Wu, Chaozhao Liang, Dianqing Wu
Autosomal dominant polycystic kidney disease (ADPKD) can be caused by mutations in the PKD1 or PKD2 genes. The PKD1 gene product is a Wnt cell-surface receptor. We previously showed that a lack of the PKD2 gene product, PC2, increases β-catenin signaling in mouse embryonic fibroblasts, kidney renal epithelia, and isolated renal collecting duct cells. However, it remains unclear whether β-catenin signaling plays a role in polycystic kidney disease phenotypes or if a Wnt inhibitor can halt cyst formation in ADPKD disease models...
March 8, 2018: JCI Insight
Ebony M Flowers, Jessica Sudderth, Lauren Zacharias, Glenda Mernaugh, Roy Zent, Ralph J DeBerardinis, Thomas J Carroll
Polycystic kidney disease (PKD) is a common genetic disorder characterized by the growth of fluid-filled cysts in the kidneys. Several studies reported that the serine-threonine kinase Lkb1 is dysregulated in PKD. Here we show that genetic ablation of Lkb1 in the embryonic ureteric bud has no effects on tubule formation, maintenance, or growth. However, co-ablation of Lkb1 and Tsc1, an mTOR repressor, results in an early developing, aggressive form of PKD. We find that both loss of Lkb1 and loss of Pkd1 render cells dependent on glutamine for growth...
February 26, 2018: Nature Communications
Yubin Shin, Do Yeon Kim, Je Yeong Ko, Yu Mi Woo, Jong Hoon Park
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited disorders. ADPKD is caused by mutations in the gene encoding either polycystic kidney disease 1 ( PKD1) or polycystic kidney disease 2 ( PKD2). Patients with ADPKD show progressive growth of cystic fluid-filled renal cysts. Here, we used Pkd2f/f control mice and Pkd2f/f :HoxB7-Cre experimental mice, which are bred to have a conditional deletion of Pkd2 in the collecting ducts, and analyzed the expression pattern of microRNAs (miRNAs) of kidney tissues from Pkd2f/f and Pkd2f/f :HoxB7-Cre mice...
February 16, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Aditya Ganju, Subhash C Chauhan, Bilal Bin Hafeez, Kyle Doxtater, Manish K Tripathi, Nadeem Zafar, Murali M Yallapu, Rakesh Kumar, Meena Jaggi
BACKGROUND: Cancer progression and metastasis is profoundly influenced by protein kinase D1 (PKD1) and metastasis-associated protein 1 (MTA1) in addition to other pathways. However, the nature of regulatory relationship between the PKD1 and MTA1, and its resulting impact on cancer metastasis remains unknown. Here we present evidence to establish that PKD1 is an upstream regulatory kinase of MTA1. METHODS: Protein and mRNA expression of MTA1 in PKD1-overexpressing cells were determined using western blotting and reverse-transcription quantitative real-time PCR...
February 20, 2018: British Journal of Cancer
Cheng-Chao Lin, Mahiro Kurashige, Yi Liu, Takeshi Terabayashi, Yu Ishimoto, Tanchun Wang, Vineet Choudhary, Ryan Hobbs, Li-Ka Liu, Ping-Hsien Lee, Patricia Outeda, Fang Zhou, Nicholas P Restifo, Terry Watnick, Haruna Kawano, Shigeo Horie, William Prinz, Hong Xu, Luis F Menezes, Gregory G Germino
Recent studies have reported intrinsic metabolic reprogramming in Pkd1 knock-out cells, implicating dysregulated cellular metabolism in the pathogenesis of polycystic kidney disease. However, the exact nature of the metabolic changes and their underlying cause remains controversial. We show herein that Pkd1 k o /ko renal epithelial cells have impaired fatty acid utilization, abnormal mitochondrial morphology and function, and that mitochondria in kidneys of ADPKD patients have morphological alterations. We further show that a C-terminal cleavage product of polycystin-1 (CTT) translocates to the mitochondria matrix and that expression of CTT in Pkd1 ko/ko cells rescues some of the mitochondrial phenotypes...
February 9, 2018: Scientific Reports
Yuanyuan Su, Pengfeng Wang, Hong Shen, Zhaomeng Sun, Chenzhong Xu, Guodong Li, Tanjun Tong, Jun Chen
Senescent cells develop senescence-associated secretory phenotype (SASP) which possesses multiple biological functions via autocrine or paracrine manner. However, the status of the protein kinase D1 (PKD1)-mediated classical protein secretory pathway from trans-Golgi network (TGN) to cell surface during cellular senescence and its role in cellular senescent response remain unknown. Here, we show that the activities or quantities of the critical components of this pathway including PKD1, ADP-ribosylation factor 1 (ARF1), and phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ) at TGN are increased in senescent cells...
February 2, 2018: Journal of Cell Science
Anna S Nikonova, Alexander Y Deneka, Anna A Kiseleva, Vladislav Korobeynikov, Anna Gaponova, Ilya G Serebriiskii, Meghan C Kopp, Harvey H Hensley, Tamina N Seeger-Nukpezah, Stefan Somlo, David A Proia, Erica A Golemis
Autosomal-dominant polycystic kidney disease (ADPKD) is associated with progressive formation of renal cysts, kidney enlargement, hypertension, and typically end-stage renal disease. In ADPKD, inherited mutations disrupt function of the polycystins (encoded by PKD1 and PKD2), thus causing loss of a cyst-repressive signal emanating from the renal cilium. Genetic studies have suggested ciliary maintenance is essential for ADPKD pathogenesis. Heat shock protein 90 (HSP90) clients include multiple proteins linked to ciliary maintenance...
January 10, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Emilie Cornec-Le Gall, Fouad T Chebib, Charles D Madsen, Sarah R Senum, Christina M Heyer, Brendan C Lanpher, Marc C Patterson, Robert C Albright, Alan S Yu, Vicente E Torres, Peter C Harris
The diagnosis of autosomal dominant polycystic kidney disease (ADPKD) relies on imaging criteria in the setting of a positive familial history. Molecular analysis, seldom used in clinical practice, identifies a causative mutation in >90% of cases in the genes PKD1, PKD2, or rarely GANAB. We report the clinical and genetic dissection of a 7-generation pedigree, resulting in the diagnosis of 2 different cystic disorders. Using targeted next-generation sequencing of 65 candidate genes in a patient with an ADPKD-like phenotype who lacked the familial PKD2 mutation, we identified a COL4A1 mutation (p...
January 27, 2018: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
Julia Pose-Utrilla, Lucía García-Guerra, Ana Del Puerto, Abraham Martín, Jerónimo Jurado-Arjona, Noelia S De León-Reyes, Andrea Gamir-Morralla, Álvaro Sebastián-Serrano, Mónica García-Gallo, Leonor Kremer, Jens Fielitz, Christofer Ireson, Mª José Pérez-Álvarez, Isidro Ferrer, Félix Hernández, Jesús Ávila, Marina Lasa, Miguel R Campanero, Teresa Iglesias
The original version of this Article contained an error in the spelling of the author Álvaro Sebastián-Serrano, which was incorrectly given as Álvaro Sebastián Serrano. This has now been corrected in both the PDF and HTML versions of the Article.
January 30, 2018: Nature Communications
Sonam Raj, Rana Gopal Singh, Parimal Das
Polycystic kidney disease (PKD) is a systemic disorder which adds majority of renal patients to end stage renal disease. Autosomal dominant polycystic kidney disease (ADPKD) is more prevalent and leading cause of dialysis and kidney transplant. Linkage analysis revealed some closely linked loci, two of which are identified as PKD1, PKD2 and an unidentified locus to ADPKD. This study was performed using PCR and automated DNA sequencing in 84 cases and 80 controls to test potential candidature of PKD2 as underlying cause of PKD by in silico and statistical analyses...
December 2017: Journal of Genetics
Godela M Brosnahan, Kaleab Z Abebe, Charity G Moore, Frederic F Rahbari-Oskoui, Kyongtae T Bae, Jared J Grantham, Robert W Schrier, William E Braun, Arlene B Chapman, Michael F Flessner, Peter C Harris, Marie C Hogan, Ronald D Perrone, Dana C Miskulin, Theodore I Steinman, Vicente E Torres
BACKGROUND: Previous clinical studies of autosomal dominant polycystic kidney disease (ADPKD) reported that loss of kidney function usually follows a steep and relentless course. A detailed examination of individual patterns of decline in estimated glomerular filtration rate (eGFR) has not been performed. STUDY DESIGN: Longitudinal post hoc analysis of data collected during the Halt Progression of Polycystic Kidney Disease (HALT-PKD) trials. SETTING & PARTICIPANTS: 494 HALT-PKD Study A participants (younger; preserved eGFR) and 435 Study B participants (older; reduced eGFR) who had more than 3 years of follow-up and 7 or more eGFR assessments...
January 3, 2018: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
Julia Pose-Utrilla, Lucía García-Guerra, Ana Del Puerto, Abraham Martín, Jerónimo Jurado-Arjona, Noelia S De León-Reyes, Andrea Gamir-Morralla, Álvaro Sebastián Serrano, Mónica García-Gallo, Leonor Kremer, Jens Fielitz, Christofer Ireson, Mª José Pérez-Álvarez, Isidro Ferrer, Félix Hernández, Jesús Ávila, Marina Lasa, Miguel R Campanero, Teresa Iglesias
Excitotoxicity, a critical process in neurodegeneration, induces oxidative stress and neuronal death through mechanisms largely unknown. Since oxidative stress activates protein kinase D1 (PKD1) in tumor cells, we investigated the effect of excitotoxicity on neuronal PKD1 activity. Unexpectedly, we find that excitotoxicity provokes an early inactivation of PKD1 through a dephosphorylation-dependent mechanism mediated by protein phosphatase-1 (PP1) and dual specificity phosphatase-1 (DUSP1). This step turns off the IKK/NF-κB/SOD2 antioxidant pathway...
December 22, 2017: Nature Communications
Ninel Azoitei, Mathias Cobbaut, Alexander Becher, Johan Van Lint, Thomas Seufferlein
Protein kinase D2 (PKD2) is a serine/threonine kinase that belongs to the PKD family of calcium-calmodulin kinases, which comprises three isoforms: PKD1, PKD2, and PKD3. PKD2 is activated by many stimuli including growth factors, phorbol esters, and G-protein-coupled receptor agonists. PKD2 participation to uncontrolled growth, survival, neovascularization, metastasis, and invasion has been documented in various tumor types including pancreatic, colorectal, gastric, hepatic, lung, prostate, and breast cancer, as well as glioma multiforme and leukemia...
December 20, 2017: Oncogene
Ditte Søvsø Gundelund Nielsen, Marlene Fredborg, Vibeke Andersen, Stig Purup
Inflammatory bowel diseases (IBD) are chronic inflammatory diseases involving all or part of the gastrointestinal tract. The stress-activated serine-threonine protein kinase D1 (PKD1) protein has previously been implicated in intestinal immune regulation. The objective of this study was to evaluate the effects of human PKD1 in relation to intestinal inflammation, using a co-culture model of intestinal epithelial Caco-2 cells and RAW264.7 macrophages. An inflammatory response was induced in the macrophages by lipopolysaccharide (LPS), upregulating the expression of tumour necrosis factor alpha (TNF- α ), interleukin- (IL-) 1 β , and IL-6 besides increasing the secretion of TNF- α protein...
2017: International Journal of Inflammation
Lei Wang, Shijie Zhang, Zhigao Xu, Jingjing Zhang, Li Li, Guoqiang Zhao
Acute aortic dissection (AAD) is a life-threatening cardiovascular disease with the high morbidity and mortality. Imaging modalities are the gold standard for the diagnosis of AAD; however, they are not always available in emergency department. Biomarker-assisted diagnosis is important for the early treatment of AAD. The aim of the present study was to identify potential microRNA (miRNA) biomarkers for AAD. Differentially expressed plasma miRNAs between AAD patients and age-matched healthy volunteers were analyzed by miRNA microarray...
2017: American Journal of Translational Research
Hui Yang, Qiuxia Chen, Fangyun Sun, Nana Zhao, Lirong Wen, Lin Li, Gai Ran
Resveratrol (RSV), a natural polyphenol, has been reported to produce effect on genes transcription in lipid metabolism. In this study, we aim to explore the novel mechanisms of RSV on the regulation of caveolin-1 (Cav-1) transcription. Via body weight, blood glucose, serum lipid, and liver pathology detection, we found that RSV decreased body weight, blood glucose and lipid accumulation in rats fed high-fat diet. Based on co-immunoprecipitation (Co-IP) and western blotting assay, we found that RSV up-regulated klf5 phosphorylation and decreased the interaction of klf5 with c-Myc, which were accompanied by down-regulation of Cav-1 expression in livers of rats fed with high-fat diet...
2017: PloS One
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