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Yu Mi Woo, Je Yeong Ko, Eun Ji Lee
Various polycystic kidney disease (PKD) animal models including Pkd1- or Pkd2-deficient mice have been developed and efficiently utilized to identify novel therapeutic targets as well as elucidate multiple mechanisms of cyst formation in PKD. Based on several successful in vivo studies, preclinical approaches using PKD animal models would shed light on the development of potential therapeutic strategies for PKD. Here, we provide an update on the current evidence obtained by the in vivo evaluation of PKD therapeutic candidates and discuss the effect of therapeutic targets...
2016: Advances in Experimental Medicine and Biology
Eun Ji Lee
Increased tubular epithelial cell proliferation with fluid secretion is a key hallmark of autosomal dominant polycystic kidney disease (ADPKD). With disruption of either PKD1 or PKD2, the main causative genes of ADPKD, intracellular calcium homeostasis and cAMP accumulation are disrupted, which in turn leads to altered signaling in the pathways that regulate cell proliferation. These dysregulations finally stimulate the development of fluid-filled cysts originating from abnormally proliferating renal tubular cells...
2016: Advances in Experimental Medicine and Biology
Do Yeon Kim, Jong Hoon Park
Autosomal dominant polycystic kidney disease is caused by mutation of PKD1 (polycystic kidney disease-1) or PKD2 (polycystic kidney disease-2). PKD1 and PKD2 encode PC1 (polycystin-1) and PC2 (polycystin-2), respectively. In addition, the mutation of cilia-associated proteins is also a recognized major factor of pathogenesis, since PC1 and PC2 are located in primary cilium. Abnormalities of PC1 or PC2 lead to aberrant signaling through downstream pathways, such as the negative growth regulation, G protein activation, and canonical and non-canonical Wnt pathways...
2016: Advances in Experimental Medicine and Biology
Yu Bin Shin, Jong Hoon Park
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common inherited disorders. It is the fourth leading cause of renal replacement and renal failure worldwide. Mutations in PKD1 or PKD2 cause ADPKD. Patients with ADPKD show progressive growth of renal cysts filled with cystic fluid, leading to end-stage renal disease (ESRD) and renal failure by their sixth decade of life. Currently, there are no curative treatments for ADPKD. Therefore, patients require dialysis or kidney transplantation...
2016: Advances in Experimental Medicine and Biology
Valentina Corradi, Fiorella Gastaldon, Carlotta Caprara, Anna Giuliani, Francesca Martino, Fiorenza Ferrari, Claudio Ronco
INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic diseases with a reported prevalence of 1:400 to 1:1000. Since the intact kidneys can compensate for the loss of glomerular filtration in ADPKD patients, renal insufficiency usually remains undetected until almost the fourth decade of life. Hereafter, reliable diagnostic and prognostic biomarkers to identify ADPKD progression are urgently needed. Several studies and systematic reviews tried to identify markers or predictors of rapid disease progression of ADPKD...
October 4, 2016: Minerva Medica
Clara Aicart Ramos, Sophia Dan Qing He, Marianne Land, Charles S Rubin
Protein kinase D (PKD) isoforms are protein kinase C effectors in signaling pathways regulated by diacylglycerol (DAG). Important physiological processes (including secretion, immune responses, motility and transcription) are placed under DAG control by the distinctive substrate specificity and subcellular distribution of PKDs. Potentially, broadly co-expressed PKD polypeptides may interact to generate homo- or hetero-multimeric regulatory complexes. However, the frequency, molecular basis, regulatory significance and physiological relevance of stable PKD-PKD interactions are largely unknown...
September 23, 2016: Journal of Biological Chemistry
Heike Döppler, Richard Panayiotou, Elizabeth M Reid, Willibroad Maimo, Ligia Bastea, Peter Storz
Increased expression of PRKD1 and its gene product protein kinase D1 (PKD1) are linked to oncogenic signaling in pancreatic ductal adenocarcinoma, but a direct functional relationship to oncogenic KRas has not been established so far. We here describe the PRKD1 gene promoter as a target for oncogenic KRas signaling. We demonstrate that KRas-induced activation of the canonical NF-κB pathway is one mechanism of how PRKD1 expression is increased and identify the binding sites for NF-κB in the PRKD1 promoter...
2016: Scientific Reports
Francesco Vetrini, Lisa C A D'Alessandro, Zeynep C Akdemir, Alicia Braxton, Mahshid S Azamian, Mohammad K Eldomery, Kathryn Miller, Chelsea Kois, Virginia Sack, Natasha Shur, Asha Rijhsinghani, Jignesh Chandarana, Yan Ding, Judy Holtzman, Shalini N Jhangiani, Donna M Muzny, Richard A Gibbs, Christine M Eng, Neil A Hanchard, Tamar Harel, Jill A Rosenfeld, John W Belmont, James R Lupski, Yaping Yang
Disruption of the establishment of left-right (L-R) asymmetry leads to situs anomalies ranging from situs inversus totalis (SIT) to situs ambiguus (heterotaxy). The genetic causes of laterality defects in humans are highly heterogeneous. Via whole-exome sequencing (WES), we identified homozygous mutations in PKD1L1 from three affected individuals in two unrelated families. PKD1L1 encodes a polycystin-1-like protein and its loss of function is known to cause laterality defects in mouse and medaka fish models...
October 6, 2016: American Journal of Human Genetics
Mónica Furlano, Yaima Barreiro, Teresa Martí, Carme Facundo, César Ruiz-García, Iara DaSilva, Nadia Ayasreh, Cristina Cabrera-López, José Ballarín, Elisabet Ars, Roser Torra
We report the case of a 32-year-old male diagnosed with TSC2/PKD1 contiguous gene syndrome, presenting with tuberous sclerosis (TS) and autosomal dominant polycystic kidney disease simultaneously. He progressed to end-stage renal disease and received a kidney transplant at the age of 12. The native kidneys presented angiomyolipomas (AML), which are common benign tumours in patients with TS. Seventeen years after transplantation, he presented with abdominal pain, anaemia and a retroperitoneal haematoma, the latter caused by renal AML bleeding...
August 29, 2016: Nefrología: Publicación Oficial de la Sociedad Española Nefrologia
Zhiguo Mao, Jiehan Chong, Albert C M Ong
The first clinical descriptions of autosomal dominant polycystic kidney disease (ADPKD) go back at least 500 years to the late 16 (th) century. Advances in understanding disease presentation and pathophysiology have mirrored the progress of clinical medicine in anatomy, pathology, physiology, cell biology, and genetics. The identification of PKD1 and PKD2, the major genes mutated in ADPKD, has stimulated major advances, which in turn have led to the first approved drug for this disorder and a fresh reassessment of patient management in the 21 (st) century...
2016: F1000Research
Hila Milo Rasouly, Sudhir Kumar, Stefanie Chan, Anna Pisarek-Horowitz, Richa Sharma, Qiongchao J Xi, Yuriko Nishizaki, Yujiro Higashi, David J Salant, Richard L Maas, Weining Lu
Primary glomerulocystic kidney disease is a special form of renal cystic disorder characterized by Bowman's space dilatation in the absence of tubular cysts. ZEB2 is a SMAD-interacting transcription factor involved in Mowat-Wilson syndrome, a congenital disorder with an increased risk for kidney anomalies. Here we show that deletion of Zeb2 in mesenchyme-derived nephrons with either Pax2-cre or Six2-cre causes primary glomerulocystic kidney disease without tubular cysts in mice. Glomerulotubular junction analysis revealed many atubular glomeruli in the kidneys of Zeb2 knockout mice, which explains the presence of glomerular cysts in the absence of tubular dilatation...
August 30, 2016: Kidney International
Debbie Zittema, Irina B Versteeg, Ron T Gansevoort, Harry van Goor, Emile de Heer, Kimberley A M Veraar, Dorien J M Peters, Esther Meijer
BACKGROUND: In autosomal dominant polycystic kidney disease, renoprotective treatment with a vasopressin V2 receptor antagonist (V2RA) is given in a fixed dose (FD). Disease progression and drug habituation could diminish treatment efficacy. We investigated whether the renoprotective effect of the V2RA can be improved by dose titration of the V2RA aiming to maintain aquaresis at a high level. METHODS: The V2RA OPC-31260 was administered to Pkd1-deletion mice in an FD (0...
2016: American Journal of Nephrology
Laurel Truscott, Joanna Gell, Vivian Y Chang, Hane Lee, Samuel P Strom, Rex Pillai, Anthony Sisk, Julian A Martinez-Agosto, Martin Anderson, Noah Federman
Adolescent brothers were diagnosed with testicular germ cell tumors within the same month. Both were found to have multiple renal cysts on pretreatment imaging done for staging. The proband, his brother, and their mother, were all found to have a novel splice variant in intron 8 of the PKD1 gene by clinical exome sequencing. This is the second family reported with both familial testicular germ cell tumor (FTGCT) and autosomal dominant polycystic kidney disease (ADPKD), and the first described association of FTGCT with a splice variant in PKD1...
August 31, 2016: Pediatric Blood & Cancer
Kengo Hirota, Hiroyuki Akagawa, Hideaki Onda, Taku Yoneyama, Takakazu Kawamata, Hidetoshi Kasuya
BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) caused by deleterious mutations in PKD1 (16p13.3) and PKD2 (4q21) often coexists with intracranial aneurysms (IAs). In this study, we investigated whether IAs without obvious renal diseases were also associated with these ADPKD genes. METHODS: We performed next-generation sequencing of the ADPKD genes in 150 Japanese familial IA patients and age- and sex-matched 150 non-IA controls without obvious renal diseases...
August 24, 2016: Journal of Stroke and Cerebrovascular Diseases: the Official Journal of National Stroke Association
Andre Kraus, Steffen Grampp, Margarete Goppelt-Struebe, Rainer Schreiber, Karl Kunzelmann, Dorien J M Peters, Jens Leipziger, Gunnar Schley, Johannes Schödel, Kai-Uwe Eckardt, Bjoern Buchholz
Polycystic kidney diseases are characterized by numerous renal cysts that continuously enlarge resulting in compression of intact nephrons and tissue hypoxia. Recently, we have shown that hypoxia-inducible factor (HIF)-1α promotes secretion-dependent cyst expansion, presumably by transcriptional regulation of proteins that are involved in calcium-activated chloride secretion. Here, we report that HIF-1α directly activates expression of the purinergic receptor P2Y2R in human primary renal tubular cells. In addition, we found that P2Y2R is highly expressed in cyst-lining cells of human ADPKD kidneys as well as PKD1 orthologous mouse kidneys...
August 26, 2016: Purinergic Signalling
G K Rangan, M C Tchan, A Tong, A T Y Wong, B J Nankivell
Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease in adults, affecting one in every 1000 Australians. It is caused by loss-of-function heterozygous mutations in either PKD1 or PKD2 , which encode the proteins, polycystin-1 and polycystin-2 respectively. The disease hallmark is the development of hundreds of microscopic fluid-filled cysts in the kidney during early childhood, which grow exponentially and continuously through life at varying rates (between 2% and 10% per year), causing loss of normal renal tissue and up to a 50% lifetime risk of dialysis-dependent kidney failure...
August 2016: Internal Medicine Journal
Edgar S Wills, Wybrich R Cnossen, Joris A Veltman, Rob Woestenenk, Marloes Steehouwer, Jody Salomon, René H M Te Morsche, Meritxell Huch, Jayne Y Hehir-Kwa, Martijn J Banning, Rolph Pfundt, Ronald Roepman, Alexander Hoischen, Joost P H Drenth
Autosomal dominant polycystic liver disease (ADPLD) is caused by variants in PRKCSH, SEC63, and LRP5, whereas autosomal dominant polycystic kidney disease is caused by variants in PKD1 and PKD2. Liver cyst development in these disorders is explained by somatic loss-of-heterozygosity (LOH) of the wild-type allele in the developing cyst. We hypothesize that we can use this mechanism to identify novel disease genes that reside in LOH regions. In this study, we aim to map abnormal genomic regions using high-density SNP microarrays to find novel PLD genes...
August 24, 2016: European Journal of Human Genetics: EJHG
Kazeem Olalekan, Andy Fox, Rodney Gilbert
BACKGROUND: Unlicensed medications are used all the time in the management of diseases in childhood. Tolvaptan (Jinarc®) is a vasopressin V2-receptor antagonist licensed for use to slow the progression of cyst development and renal insufficiency of ADPKD in adults with CKD stage 1 to 3 with evidence of rapidly progressing disease. Studies of animal models implicate the antidiuretic hormone arginine vasopressin and its messenger cyclic adenosine monophosphate (cAMP) as promoters of kidney-cyst cell proliferation and luminal fluid secretion...
September 2016: Archives of Disease in Childhood
Weihua Qiu, Susan F Steinberg
Protein kinase D (PKD) consists of a family of three structurally related enzymes that are co-expressed in the heart and have important roles in many biological responses. PKD1 is activated by pro-hypertrophic stimuli and has been implicated in adverse cardiac remodeling. Efforts to define the cardiac actions of PKD2 and PKD3 have been less successful at least in part because conventional methods provide a general screen for PKD activation but are poorly suited to resolve activation patterns for PKD2 or PKD3...
August 8, 2016: Journal of Molecular and Cellular Cardiology
Yong Wu, Jen X Xu, Wassim El-Jouni, Tzongshi Lu, Suyan Li, Qingyi Wang, Mei Tran, Wanfeng Yu, Maoqing Wu, Ivan E Barrera, Joseph V Bonventre, Jing Zhou, Bradley M Denker, Tianqing Kong
Mutation of PKD1, encoding the protein polycystin-1 (PC1), is the main cause of autosomal dominant polycystic kidney disease (ADPKD). The signaling pathways downstream of PC1 in ADPKD are still not fully understood. Here, we provide genetic evidence for the necessity of Gα12 (encoded by Gna12, hereafter Gα12) for renal cystogenesis induced by Pkd1 knockout. There was no phenotype in mice with deletion of Gα12 (Gα12(-/-)). Polyinosine-polycytosine (pI:pC)-induced deletion of Pkd1 (Mx1Cre(+)Pkd1(f/f)Gα12(+/+)) in 1-week-old mice resulted in multiple kidney cysts by 9 weeks, but the mice with double knockout of Pkd1 and Gα12 (Mx1Cre(+)Pkd1(f/f)Gα12(-/-)) had no structural and functional abnormalities in the kidneys...
October 1, 2016: Journal of Cell Science
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