22 results on '"Park, Jong Hoon"'
Search Results
2. TAZ/Wnt-β-catenin/c-MYC axis regulates cystogenesis in polycystic kidney disease.
- Author
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Lee EJ, Seo E, Kim JW, Nam SA, Lee JY, Jun J, Oh S, Park M, Jho EH, Yoo KH, Park JH, and Kim YK
- Subjects
- Adaptor Proteins, Signal Transducing, Animals, Axin Protein, Cell Proliferation, Disease Models, Animal, Epithelial Cells metabolism, Humans, Kidney metabolism, Kidney pathology, Mice, Mice, Knockout, Polycystic Kidney Diseases pathology, Polycystic Kidney, Autosomal Dominant genetics, Polycystic Kidney, Autosomal Dominant pathology, Protein Kinase C deficiency, Protein Kinase C genetics, TRPP Cation Channels genetics, Transcriptome, Polycystic Kidney Diseases genetics, Polycystic Kidney Diseases metabolism, Polycystic Kidney, Autosomal Dominant metabolism, Proto-Oncogene Proteins c-myc metabolism, Trans-Activators metabolism, Wnt Signaling Pathway physiology, beta Catenin metabolism
- Abstract
Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, primarily caused by germline mutation of PKD1 or PKD2 , leading to end-stage renal disease. The Hippo signaling pathway regulates organ growth and cell proliferation. Herein, we demonstrate the regulatory mechanism of cystogenesis in ADPKD by transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo signaling effector. TAZ was highly expressed around the renal cyst-lining epithelial cells of Pkd1 -deficient mice. Loss of Taz in Pkd1 -deficient mice reduced cyst formation. In wild type, TAZ interacted with PKD1, which inactivated β-catenin. In contrast, in PKD1-deficient cells, TAZ interacted with AXIN1, thus increasing β-catenin activity. Interaction of TAZ with AXIN1 in PKD1-deficient cells resulted in nuclear accumulation of TAZ together with β-catenin, which up-regulated c-MYC expression. Our findings suggest that the PKD1-TAZ-Wnt-β-catenin-c-MYC signaling axis plays a critical role in cystogenesis and might be a potential therapeutic target against ADPKD., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)
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- 2020
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3. Impact of miR-192 and miR-194 on cyst enlargement through EMT in autosomal dominant polycystic kidney disease.
- Author
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Kim DY, Woo YM, Lee S, Oh S, Shin Y, Shin JO, Park EY, Ko JY, Lee EJ, Bok J, Yoo KH, and Park JH
- Subjects
- Animals, Antigens, CD genetics, Antigens, CD metabolism, Cadherins genetics, Cadherins metabolism, Case-Control Studies, DNA Methylation, Disease Models, Animal, Gene Expression Profiling, Genome-Wide Association Study, Humans, Mice, Mice, Knockout, Polycystic Kidney, Autosomal Dominant genetics, Polycystic Kidney, Autosomal Dominant metabolism, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Zinc Finger E-box Binding Homeobox 2 genetics, Zinc Finger E-box Binding Homeobox 2 metabolism, Epithelial-Mesenchymal Transition, Gene Expression Regulation, MicroRNAs genetics, Polycystic Kidney, Autosomal Dominant pathology, Protein Serine-Threonine Kinases physiology
- Abstract
Altered miRNA (miR) expression occurs in various diseases. However, the therapeutic effect of miRNAs in autosomal dominant polycystic kidney disease (ADPKD) is unclear. Genome-wide analyses of miRNA expression and DNA methylation status were conducted to identify crucial miRNAs in end-stage ADPKD. miR-192 and -194 levels were down-regulated with hypermethylation at these loci, mainly in the intermediate and late stages, not in the early stage, of cystogenesis, suggesting their potential impact on cyst expansion. Cyst expansion has been strongly associated with endothelial-mesenchymal transition (EMT). Zinc finger E-box-binding homeobox-2 and cadherin-2, which are involved in EMT, were directly regulated by miR-192 and -194. The therapeutic effect of miR-192 and -194 in vivo and in vitro were assessed. Restoring these miRs by injection of precursors influenced the reduced size of cysts in Pkd1 conditional knockout mice. miR-192 and -194 may act as potential therapeutic targets to control the expansion and progression of cysts in patients with ADPKD.-Kim, D. Y., Woo, Y. M., Lee, S., Oh, S., Shin, Y., Shin, J.-O., Park, E. Y., Ko, J. Y., Lee, E. J., Bok, J., Yoo, K. H., Park, J. H. Impact of miR-192 and miR-194 on cyst enlargement through EMT in autosomal dominant polycystic kidney disease.
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- 2019
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4. Profiling of miRNAs and target genes related to cystogenesis in ADPKD mouse models.
- Author
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Woo YM, Kim DY, Koo NJ, Kim YM, Lee S, Ko JY, Shin Y, Kim BH, Mun H, Choi S, Lee EJ, Shin JO, Park EY, Bok J, and Park JH
- Subjects
- Actin Cytoskeleton genetics, Actin Cytoskeleton metabolism, Animals, Disease Models, Animal, Gene Expression Regulation, Homeodomain Proteins genetics, Mice, Knockout, Mice, Transgenic, MicroRNAs metabolism, Polycystic Kidney, Autosomal Dominant pathology, Protein Kinase C genetics, Reproducibility of Results, TRPP Cation Channels genetics, Wiskott-Aldrich Syndrome Protein Family genetics, rac GTP-Binding Proteins genetics, Cysts genetics, MicroRNAs genetics, Polycystic Kidney, Autosomal Dominant genetics, Transcriptome
- Abstract
Autosomal polycystic kidney disease (ADPKD) is a common inherited renal disease characterized by the development of numerous fluid-filled cysts in both kidneys. We investigated miRNA-mediated regulatory systems and networks that play an important role during cystogenesis through integrative analysis of miRNA- and RNA-seq using two ADPKD mouse models (conditional Pkd1- or Pkd2-deficient mice), at three different time points (P1, P3, and P7). At each time point, we identified 13 differentially expressed miRNAs (DEmiRs) and their potential targets in agreement with cyst progression in both mouse models. These targets were involved in well-known signaling pathways linked to cystogenesis. More specifically, we found that the actin cytoskeleton pathway was highly enriched and connected with other well-known pathways of ADPKD. We verified that miR-182-5p regulates actin cytoskeleton rearrangement and promotes ADPKD cystogenesis by repressing its target genes-Wasf2, Dock1, and Itga4-in vitro and in vivo. Our data suggest that actin cytoskeleton may play an important role in renal cystogenesis, and miR-182-5p is a novel regulator of actin cytoskeleton and cyst progression. Furthermore, this study provides a systemic network of both key miRNAs and their targets associated with cyst growth in ADPKD.
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- 2017
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5. Recent Trends in ADPKD Research.
- Author
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Shin YB and Park JH
- Subjects
- Animals, Cell Proliferation, Epigenesis, Genetic, Humans, MicroRNAs genetics, Signal Transduction, Biomedical Research trends, Polycystic Kidney, Autosomal Dominant genetics, Polycystic Kidney, Autosomal Dominant pathology
- Abstract
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. To date, researchers have elucidated many of the mechanisms that cause ADPKD and developed many methods to diagnose the disease. ADPKD is related to growth factors, signaling pathways, cell proliferation, apoptosis, inflammation, the immune system, structural abnormalities, epigenetic mechanisms, microRNAs, and so on. Various therapies have been reported to slow the progression of ADPKD and alleviate its symptoms.
- Published
- 2016
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6. Inflammation and Fibrosis in ADPKD.
- Author
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Mun H and Park JH
- Subjects
- Animals, Fibrosis, Humans, Inflammation complications, Polycystic Kidney, Autosomal Dominant complications, Polycystic Kidney, Autosomal Dominant pathology
- Abstract
Diverse signaling pathways have been reported to be associated with polycystic kidney disease (PKD). Cell proliferation is widely known to be an important pathway related to this disease. However, studies on the interactions of inflammation and fibrosis with polycystic kidney disease have been limited. Inflammation is one of the protective systems involved in the response to foreign molecules. In PKD, it was reported that the activity of signaling pathways associated with inflammation is increased. Also, fibrosis is the development of excess fibrous tissue in organ or tissue. It is an abnormal phenomenon in which the extent of fibrous connective tissues is increased. In PKD, increases in the activity of molecules such as growth factor and TGF-β have been reported to occur and promote fibrosis. Therefore, the inflammation and fibrosis responses have been suggested as therapeutic targets for PKD. In order to guide further studies, this review indicates the roles of inflammatory and fibrosis signaling in PKD.
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- 2016
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7. Genetic Mechanisms of ADPKD.
- Author
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Kim DY and Park JH
- Subjects
- Animals, Humans, Mutation, Polycystic Kidney, Autosomal Dominant etiology, Polycystic Kidney, Autosomal Dominant pathology, Signal Transduction, TRPP Cation Channels genetics, Polycystic Kidney, Autosomal Dominant genetics
- Abstract
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. According to the "second hit" model, an additional somatic mutation results in the expansion of cyst growth. In this chapter we discuss the genetic mechanisms and signaling pathways involved in ADPKD.
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- 2016
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8. Clinical Correlates of Mass Effect in Autosomal Dominant Polycystic Kidney Disease.
- Author
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Kim H, Park HC, Ryu H, Kim K, Kim HS, Oh KH, Yu SJ, Chung JW, Cho JY, Kim SH, Cheong HI, Lee K, Park JH, Pei Y, Hwang YH, and Ahn C
- Subjects
- Cysts epidemiology, Female, Follow-Up Studies, Humans, Liver Diseases epidemiology, Male, Middle Aged, Organ Size, Polycystic Kidney, Autosomal Dominant epidemiology, Prevalence, Prognosis, Republic of Korea epidemiology, Retrospective Studies, Cysts complications, Cysts pathology, Liver Diseases complications, Liver Diseases pathology, Polycystic Kidney, Autosomal Dominant etiology, Polycystic Kidney, Autosomal Dominant pathology
- Abstract
Mass effect from polycystic kidney and liver enlargement can result in significant clinical complications and symptoms in autosomal dominant polycystic kidney disease (ADPKD). In this single-center study, we examined the correlation of height-adjusted total liver volume (htTLV) and total kidney volume (htTKV) by CT imaging with hepatic complications (n = 461) and abdominal symptoms (n = 253) in patients with ADPKD. "Mass-effect" complications were assessed by review of medical records and abdominal symptoms, by a standardized research questionnaire. Overall, 91.8% of patients had 4 or more liver cysts on CT scans. Polycystic liver disease (PLD) was classified as none or mild (htTLV < 1,600 mL/m); moderate (1,600 ≤ htTLV <3,200 mL/m); and severe (htTLV ≥ 3,200 mL/m). The prevalence of moderate and severe PLD in our patient cohort was 11.7% (n = 54/461) and 4.8% (n = 22/461), respectively, with a female predominance in both the moderate (61.1%) and severe (95.5%) PLD groups. Pressure-related complications such as leg edema (20.4%), ascites (16.6%), and hernia (3.6%) were common, and patients with moderate to severe PLD exhibited a 6-fold increased risk (compared to no or mild PLD) for these complications in multivariate analysis. Similarly, abdominal symptoms including back pain (58.8%), flank pain (53.1%), abdominal fullness (46.5%), and dyspnea/chest-discomfort (44.3%) were very common, and patients with moderate to severe PLD exhibited a 5-fold increased risk for these symptoms. Moderate to severe PLD is a common and clinically important problem in ~16% of patients with ADPKD who may benefit from referral to specialized centers for further management.
- Published
- 2015
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9. Epigenetic silencing of the MUPCDH gene as a possible prognostic biomarker for cyst growth in ADPKD.
- Author
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Woo YM, Shin Y, Hwang JA, Hwang YH, Lee S, Park EY, Kong HK, Park HC, Lee YS, and Park JH
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- Cadherin Related Proteins, Gene Silencing, Genetic Markers genetics, Genetic Predisposition to Disease genetics, Humans, Prognosis, Reproducibility of Results, Risk Assessment methods, Sensitivity and Specificity, Cadherins genetics, Epigenesis, Genetic genetics, Kidney Diseases, Cystic genetics, Polycystic Kidney, Autosomal Dominant genetics
- Abstract
Although autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease, and is characterized by the formation of multiple fluid-filled cysts, which results in renal failure, early diagnosis and treatment of ADPKD have yet to be defined. Herein, we observed that the promoter region of the gene encoding mucin-like protocadherin (MUPCDH) was hypermethylated in the renal tissue of patients with ADPKD compared to non-ADPKD controls. Inversely, MUPCDH was significantly repressed in ADPKD, especially in cyst-lining cells. Our results indicate that aberrant methylation of MUPCDH promoter CpG islands may be negatively correlated with reduced expression level of MUPCDH and that this contributes to abnormal cell proliferation in ADPKD. It suggests that methylation status of MUPCDH promoter can be used as a novel epigenetic biomarker and a therapeutic target in ADPKD.
- Published
- 2015
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10. Soluble receptor for advanced glycation end products inhibits disease progression in autosomal dominant polycystic kidney disease by down-regulating cell proliferation.
- Author
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Lee EJ, Park EY, Mun H, Chang E, Ko JY, Kim DY, and Park JH
- Subjects
- Animals, Cell Line, Disease Progression, Fibrosis metabolism, Fibrosis pathology, Humans, Inflammation metabolism, Inflammation pathology, Kidney metabolism, Kidney pathology, Mice, Receptor for Advanced Glycation End Products, Cell Proliferation physiology, Down-Regulation physiology, Kidney Failure, Chronic metabolism, Kidney Failure, Chronic pathology, Polycystic Kidney, Autosomal Dominant metabolism, Polycystic Kidney, Autosomal Dominant pathology, Receptors, Immunologic metabolism
- Abstract
Autosomal polycystic kidney disease (ADPKD) is a highly prevalent genetic renal disorder in which epithelial-lining fluid-filled cysts appear in kidneys. It is accompanied by hyperactivation of cell proliferation, interstitial inflammation, and fibrosis around the cyst lining cells, finally reaching end-stage renal disease. Previously, we found high expression of ligands stimulating the receptor for advanced glycation end products (RAGE) in ADPKD mice. Furthermore, gene silencing of RAGE was revealed to cause reduction of cystogenesis via down-regulation of cell proliferation in vitro, and intravenous administration of anti-RAGE adenovirus in vivo also displayed alleviation of the disease. Here, we attempted to identify the role of soluble RAGE (sRAGE) in inhibiting the progression of ADPKD using 2 different ADPKD mouse models. sRAGE is an endogenously expressed form of RAGE that has no membrane-anchoring domain, thereby giving it the ability to neutralize the ligands that stimulate RAGE signals. Both overexpression of sRAGE and sRAGE treatment blocked RAGE-mediated cell proliferation in vitro. In addition, sRAGE-injected ADPKD mice showed reduced cysts accompanied by enhanced renal function, inhibition of cell proliferation, inflammation, and fibrosis. These positive therapeutic effects of sRAGE displayed little liver toxicity, suggesting it as a new potential therapeutic target of ADPKD with low side effects., (© FASEB.)
- Published
- 2015
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11. Restoring multidrug resistance-associated protein 3 attenuates cell proliferation in the polycystic kidney.
- Author
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Chang E, Park EY, Woo Ym, Kang DH, Hwang YH, Ahn C, and Park JH
- Subjects
- Animals, Case-Control Studies, Disease Models, Animal, Dogs, Extracellular Signal-Regulated MAP Kinases metabolism, Gene Expression Regulation, Kidney pathology, MAP Kinase Kinase Kinases metabolism, Madin Darby Canine Kidney Cells, Multidrug Resistance-Associated Proteins genetics, Polycystic Kidney, Autosomal Dominant genetics, Polycystic Kidney, Autosomal Dominant pathology, Polycystic Kidney, Autosomal Dominant therapy, Proto-Oncogene Proteins B-raf metabolism, RNA Interference, Signal Transduction, Time Factors, Transfection, Cell Proliferation, Kidney metabolism, Multidrug Resistance-Associated Proteins metabolism, Polycystic Kidney, Autosomal Dominant metabolism
- Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by abnormal proliferation of renal tubular epithelial cells, resulting in the loss of renal function. Despite identification of the genes responsible for ADPKD, few effective drugs are currently available for the disease. Thus finding additional effective drug targets is necessary. The functions of multidrug- resistance-associated protein 3 (MRP3) have been reported only in the field of drug resistance, and the renal functions of MRP3 are mostly unknown. In this study, we found that MRP3 was significantly downregulated in kidneys of human patients with ADPKD and polycystic kidney disease (PKD) mouse models. Our results suggest that downregulated MRP3 stimulated renal epithelial cell proliferation through the B-Raf/MEK/ERK signaling pathway. In contrast, we found that restoring MRP3 reduced cell proliferation and cystogenesis in vitro. These results suggest that the renal function of MRP3 is related to renal cell proliferation and cyst formation and that restoring MRP3 may be an effective therapeutic approach for PKD., (Copyright © 2015 the American Physiological Society.)
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- 2015
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12. Blockade of interleukin-8 receptor signalling inhibits cyst development in vitro, via suppression of cell proliferation in autosomal polycystic kidney disease.
- Author
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Lee EJ, Song SA, Mun HW, Yoo KH, Choi SY, Park EY, and Park JH
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- Cells, Cultured, Humans, Polycystic Kidney, Autosomal Dominant pathology, Cell Proliferation drug effects, Interleukin-8 physiology, Polycystic Kidney, Autosomal Dominant drug therapy, Polycystic Kidney, Autosomal Dominant etiology, Receptors, Interleukin-8 antagonists & inhibitors, Signal Transduction drug effects
- Abstract
Aim: Autosomal dominant polycystic kidney disease (ADPKD) is a highly prevalent inherited disorder and results in the progressive development of cysts in both kidneys. In recent studies, several cytokines and growth factors secreted by the cyst-lining epithelia were identified to be upregulated and promote cyst growth. According to our previous study, chemokines with a similar amino acid sequence as human interleukin-8 (IL-8) are highly expressed in a rodent model with renal cysts. Therefore, in this study, we focused on whether IL-8 signalling is associated with renal cyst formation, and tested the possibility of IL-8 as a new therapeutic target for ADPKD., Methods: Expression of IL-8 and its receptor were screened either by enzyme linked immunosorbent assay (ELISA) or Western blot. Inhibited IL-8 signalling by antagonist for IL-8 receptor or gene silencing was tested in molecular levels, mainly through Western blot. And cell proliferation was measured by XTT assays. Finally, a three-dimensional culture was performed to understand how IL-8 affected cyst formation, in vitro., Results: Interleukin-8 secretion and expression of its receptor highly increased in two different human ADPKD cell lines (WT9-7 and WT9-12), compared to normal human renal cortical epithelial cell line. Cell proliferation, which is mediated by IL-8 signal, was inhibited either by an antagonist or siRNA targeting for IL-8 receptor. Finally, a three-dimensional culture showed an alleviation of cystogenesis in vitro, after blocking the IL-8 receptor signals., Conclusion: These results suggest that IL-8 and its signalling molecules could be new biomarkers and a therapeutic target of ADPKD., (© 2014 Asian Pacific Society of Nephrology.)
- Published
- 2014
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13. Targeting of receptor for advanced glycation end products suppresses cyst growth in polycystic kidney disease.
- Author
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Park EY, Kim BH, Lee EJ, Chang E, Kim DW, Choi SY, and Park JH
- Subjects
- Adenoviridae genetics, Animals, Cell Line, Cell Proliferation, Cysts genetics, Cysts pathology, Cysts physiopathology, Extracellular Signal-Regulated MAP Kinases metabolism, Gene Knockdown Techniques, Humans, Kidney Function Tests, Mice, Polycystic Kidney, Autosomal Dominant genetics, Polycystic Kidney, Autosomal Dominant pathology, Polycystic Kidney, Autosomal Dominant physiopathology, Protein Kinase D2, Protein Kinases deficiency, Protein Kinases genetics, Receptor for Advanced Glycation End Products, Receptors, Immunologic deficiency, Receptors, Immunologic genetics, Signal Transduction, Cysts drug therapy, Molecular Targeted Therapy, Polycystic Kidney, Autosomal Dominant drug therapy, Receptors, Immunologic metabolism
- Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disorder. Although a myriad of research groups have attempted to identify a new therapeutic target for ADPKD, no drug has worked well in clinical trials. Our research group has focused on the receptor for advanced glycation end products (RAGE) gene as a novel target for ADPKD. This gene is involved in inflammation and cell proliferation. We have already confirmed that blocking RAGE function attenuates cyst growth in vitro. Based on this previous investigation, our group examined the effect of RAGE on cyst enlargement in vivo. PC2R mice, a severe ADPKD mouse model that we generated, were utilized. An adenovirus containing anti-RAGE shRNA was injected intravenously into this model. We observed that RAGE gene knockdown resulted in loss of kidney weight and volume. Additionally, the cystic area that originated from different nephron segments decreased in size because of down-regulation of the RAGE gene. Blood urea nitrogen and creatinine values tended to be lower after inhibiting RAGE. Based on these results, we confirmed that the RAGE gene could be an effective target for ADPKD treatment.
- Published
- 2014
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14. Genome-wide methylation profiling of ADPKD identified epigenetically regulated genes associated with renal cyst development.
- Author
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Woo YM, Bae JB, Oh YH, Lee YG, Lee MJ, Park EY, Choi JK, Lee S, Shin Y, Lyu J, Jung HY, Lee YS, Hwang YH, Kim YJ, and Park JH
- Subjects
- Animals, Cell Line, Chromatin Immunoprecipitation, Comparative Genomic Hybridization, Computational Biology, Cysts pathology, Dogs, Down-Regulation, Gene Expression Profiling, Gene Silencing, Humans, Madin Darby Canine Kidney Cells, Mutation, Polycystic Kidney, Autosomal Dominant pathology, RNA genetics, RNA isolation & purification, Sequence Analysis, DNA, Signal Transduction, TRPP Cation Channels genetics, TRPP Cation Channels metabolism, Transcription Factors genetics, Transcription Factors metabolism, Cysts genetics, DNA Methylation, Epigenesis, Genetic, Genome-Wide Association Study, Kidney pathology, Polycystic Kidney, Autosomal Dominant genetics
- Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is a common human genetic disease characterized by the formation of multiple fluid-filled cysts in bilateral kidneys. Although mutations in polycystic kidney disease 1 (PKD1) are predominantly responsible for ADPKD, the focal and sporadic property of individual cystogenesis suggests another molecular mechanism such as epigenetic alterations. To determine the epigenomic alterations in ADPKD and their functional relevance, ADPKD and non-ADPKD individuals were analyzed by unbiased methylation profiling genome-wide and compared with their expression data. Intriguingly, PKD1 and other genes related to ion transport and cell adhesion were hypermethylated in gene-body regions, and their expressions were downregulated in ADPKD, implicating epigenetic silencing as the key mechanism underlying cystogenesis. Especially, in patients with ADPKD, PKD1 was hypermethylated in gene-body region and it was associated with recruitment of methyl-CpG-binding domain 2 proteins. Moreover, treatment with DNA methylation inhibitors retarded cyst formation of Madin-Darby Canine Kidney cells, accompanied with the upregulation of Pkd1 expression. These results are consistent with previous studies that knock-down of PKD1 was sufficient for cystogenesis. Therefore, our results reveal a critical role for hypermethylation of PKD1 and cystogenesis-related regulatory genes in cyst development, suggesting epigenetic therapy as a potential treatment for ADPKD.
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- 2014
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15. Inactivation of max-interacting protein 1 induces renal cilia disassembly through reduction in levels of intraflagellar transport 20 in polycystic kidney.
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Ko JY, Yoo KH, Song SA, Kim DY, Kong HK, Ahn C, Lee HW, Kang DH, Oh GT, and Park JH
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- Animals, Basic Helix-Loop-Helix Transcription Factors genetics, Carrier Proteins genetics, Cells, Cultured, Cilia metabolism, Cilia ultrastructure, Embryo, Mammalian metabolism, Embryo, Mammalian ultrastructure, Fibroblasts metabolism, Fibroblasts ultrastructure, Gene Expression Regulation genetics, Kidney ultrastructure, Mice, Mice, Mutant Strains, Microscopy, Electron, Scanning, Polycystic Kidney, Autosomal Dominant genetics, Polycystic Kidney, Autosomal Dominant pathology, Polymerase Chain Reaction, Proto-Oncogene Protein c-ets-1 genetics, Proto-Oncogene Protein c-ets-1 metabolism, Response Elements genetics, Tumor Suppressor Proteins genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Carrier Proteins biosynthesis, Kidney metabolism, Polycystic Kidney, Autosomal Dominant metabolism, Tumor Suppressor Proteins metabolism
- Abstract
Cilia in ciliated cells consist of protruding structures that sense mechanical and chemical signals from the extracellular environment. Cilia are assembled with variety molecules via a process known as intraflagellar transport (IFT). What controls the length of cilia in ciliated cells is critical to understand ciliary disease such as autosomal dominant polycystic kidney disease, which involves abnormally short cilia. But this control mechanism is not well understood. Previously, multiple tubular cysts have been observed in the kidneys of max-interacting protein 1 (Mxi1)-deficient mice aged 6 months or more. Here, we clarified the relationship between Mxi1 inactivation and cilia disassembly. Cilia phenotypes were observed in kidneys of Mxi1-deficient mice using scanning electron microscopy to elucidate the effect of Mxi1 on renal cilia phenotype, and cilia disassembly was observed in Mxi1-deficient kidney. In addition, genes related to cilia were validated in vitro and in vivo using quantitative PCR, and Ift20 was selected as a candidate gene in this study. The length of cilium decreased, and p-ERK level induced by a cilia defect increased in kidneys of Mxi1-deficient mice. Ciliogenesis of Mxi1-deficient mouse embryonic fibroblasts (MEFs) decreased, and this abnormality was restored by Mxi1 transfection in Mxi1-deficient MEFs. We confirmed that ciliogenesis and Ift20 expression were regulated by Mxi1 in vitro. We also determined that Mxi1 regulates Ift20 promoter activity via Ets-1 binding to the Ift20 promoter. These results indicate that inactivating Mxi1 induces ciliary defects in polycystic kidney.
- Published
- 2013
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16. Effects of specific genes activating RAGE on polycystic kidney disease.
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Park EY, Seo MJ, and Park JH
- Subjects
- Animals, Calgranulin A biosynthesis, Calgranulin B biosynthesis, Gene Expression, Inflammation, Intracellular Signaling Peptides and Proteins metabolism, Kidney Tubules pathology, Mice, Mice, Transgenic, Microarray Analysis, NF-kappa B metabolism, Nephritis, Interstitial metabolism, Nephritis, Interstitial pathology, Polycystic Kidney, Autosomal Dominant immunology, Polycystic Kidney, Autosomal Dominant pathology, Receptor for Advanced Glycation End Products, Receptors, Immunologic biosynthesis, Up-Regulation, Calgranulin A genetics, Calgranulin B genetics, Cytokines metabolism, Intracellular Signaling Peptides and Proteins genetics, NF-kappa B genetics, Polycystic Kidney, Autosomal Dominant genetics, Receptors, Immunologic genetics
- Abstract
Background: Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation and secretion of fluid and is associated with interstitial inflammation and fibrosis, resulting in the loss of renal function. We previously generated mice overexpressing PKD2, causing progressive cyst development with an inflammatory and fibrotic phenotype in the kidneys., Methods: To profile the gene expression related to inflammation and cystogenesis, microarray analysis was performed with kidney tissue from 6-, 12- and 18-month-old mice. Subsequently, levels and related mechanisms of selected genes, s100a8 and s100a9, were evaluated., Results: S100a8 and s100a9 was upregulated more than 2-fold and differently expressed in the cystic region. Receptor of advanced glycation end product (RAGE) is a putative cell surface receptor for s100a8/a9. It was expressed in cyst-lining cells and up-regulated pro-inflammatory transcription factor NF-kappaB in transgenic mice. We also confirmed RAGE expression in ADPKD patient kidneys. It was suggested that the signaling related to proliferative cystogenesis through previous reports; therefore, we confirmed that phosphorylated-ERK and cyst formation was reduced by treatment of RAGE-siRNA., Conclusions: The results may provide important information for the expression of s100a8/a9 and RAGE, linking progressive cystogenesis with inflammation in cystic kidney., (2010 S. Karger AG, Basel.)
- Published
- 2010
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17. Cyst formation in kidney via B-Raf signaling in the PKD2 transgenic mice.
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Park EY, Sung YH, Yang MH, Noh JY, Park SY, Lee TY, Yook YJ, Yoo KH, Roh KJ, Kim I, Hwang YH, Oh GT, Seong JK, Ahn C, Lee HW, and Park JH
- Subjects
- Animals, Apoptosis genetics, Cell Proliferation, Cysts genetics, Cysts pathology, Disease Models, Animal, Extracellular Signal-Regulated MAP Kinases genetics, Extracellular Signal-Regulated MAP Kinases metabolism, Female, Humans, Kidney pathology, Male, Mice, Mice, Inbred ICR, Mice, Transgenic, Mitogen-Activated Protein Kinase Kinases genetics, Mitogen-Activated Protein Kinase Kinases metabolism, Phenotype, Polycystic Kidney, Autosomal Dominant genetics, Polycystic Kidney, Autosomal Dominant pathology, Proto-Oncogene Proteins B-raf genetics, TRPP Cation Channels genetics, Cysts metabolism, Kidney metabolism, Mutation, Polycystic Kidney, Autosomal Dominant metabolism, Proto-Oncogene Proteins B-raf metabolism, Signal Transduction, TRPP Cation Channels biosynthesis
- Abstract
The pathogenic mechanisms of human autosomal dominant polycystic kidney disease (ADPKD) have been well known to include the mutational inactivation of PKD2. Although haploinsufficiency and loss of heterozygosity at the Pkd2 locus can cause cyst formation in mice, polycystin-2 is frequently expressed in the renal cyst of human ADPKD, raising the possibility that deregulated activation of PKD2 may be associated with the cystogenesis of human ADPKD. To determine whether increased PKD2 expression is physiologically pathogenic, we generated PKD2-overexpressing transgenic mice. These mice developed typical renal cysts and an increase of proliferation and apoptosis, which are reflective of the human ADPKD phenotype. These manifestations were first observed at six months, and progressed with age. In addition, we found that ERK activation was induced by PKD2 overexpression via B-Raf signaling, providing a possible molecular mechanism of cystogenesis. In PKD2 transgenic mice, B-Raf/MEK/ERK sequential signaling was up-regulated. Additionally, the transgenic human polycystin-2 partially rescues the lethality of Pkd2 knock-out mice and therefore demonstrates that the transgene generated a functional product. Functional strengthening or deregulated activation of PKD2 may be a direct cause of ADPKD. The present study provides evidence for an in vivo role of overexpressed PKD2 in cyst formation. This transgenic mouse model should provide new insights into the pathogenic mechanism of human ADPKD.
- Published
- 2009
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18. NCAM as a cystogenesis marker gene of PKD2 overexpression.
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Yoo KH, Lee TY, Yang MH, Park EY, Yook YJ, Lee HS, and Park JH
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- Cell Line, Gene Expression, Gene Expression Profiling, Genes, myc, Genetic Markers, Humans, Kidney metabolism, Oligonucleotide Array Sequence Analysis, Polycystic Kidney, Autosomal Dominant metabolism, Neural Cell Adhesion Molecules genetics, Polycystic Kidney, Autosomal Dominant genetics, TRPP Cation Channels metabolism
- Abstract
ADPKD (Autosomal Dominant Polycystic Kidney Disease) is characterized by the progressive expansion of multiple cystic lesions in the kidneys. ADPKD is caused by mutations in Ed-pl. consider PKD1 and PKD2. Recently a relation between c-myc and the pathogenesis of ADPKD was reported. In addition, c-Myc is a downstream effector of PKD1. To identify the gene regulated by PKD2 and c-Myc, we performed gene expression profiling in PKD2 and c-Myc overexpressing cells using a human 8K cDNA microarray. NCAM (neuronal cell adhesion molecule) levels were significantly reduced in PKD2 overexpressing systems in vitro and in vivo. These results suggest that NCAM is an important molecule in the cystogenesis induced by PKD2 overexpression.
- Published
- 2008
- Full Text
- View/download PDF
19. Expression of the Pkd1 gene is momentously regulated by Sp1.
- Author
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Jeon JO, Yoo KH, and Park JH
- Subjects
- Animals, Base Sequence, Cell Line, Female, Humans, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Promoter Regions, Genetic physiology, Protein Binding genetics, Sp1 Transcription Factor metabolism, Gene Expression Regulation physiology, Polycystic Kidney, Autosomal Dominant enzymology, Polycystic Kidney, Autosomal Dominant genetics, Sp1 Transcription Factor physiology, TRPP Cation Channels metabolism
- Abstract
Background: Autosomal dominant polycystic kidney disease (ADPKD) is a common human genetic disease that is caused by a mutation of a single gene inherited from either parent. Mutations in the Pkd1 gene result in the formation of multiple fluid-filled cysts in kidneys. In previous studies, the functional regulatory sequences of Pkd1 promoter region were detected by the use of comparative genome analysis., Methods: To investigate the transcriptional regulation of the Pkd1 gene, the Pkd1 promoter was isolated. This promoter contains three Sp1-binding sites. Two of the sites which are found in a 300 bp fragment (-127 to +157) were mutated. An electrophoretic mobility shift assay (EMSA) was performed to determine which transcription factors are bound to Pkd1., Results: Based on studies using a luciferase assay, the Sp1-A site (the nearest Sp1 to the ATG start codon) is more important for activation of Pkd1. The result of EMSA showed that Sp1 transcription factor binds with Pkd1 promoter regions., Conclusions: Two of the Sp1 sites were found in a proximal promoter region of Pkd1 (-127 to +157). Sp1 sites affect an important role in the activation of the gene. Especially, the Sp1-A site is more important for expression of Pkd1., ((c) 2007 S. Karger AG, Basel.)
- Published
- 2007
- Full Text
- View/download PDF
20. The gene expression profile of cyst epithelial cells in autosomal dominant polycystic kidney disease patients.
- Author
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Lee JE, Park MH, and Park JH
- Subjects
- Cells, Cultured, Down-Regulation, Epithelial Cells metabolism, Gene Expression Profiling, Humans, Membrane Proteins genetics, Membrane Proteins metabolism, Polycystic Kidney, Autosomal Dominant metabolism, Reverse Transcriptase Polymerase Chain Reaction, TRPP Cation Channels, Up-Regulation, Gene Expression, Polycystic Kidney, Autosomal Dominant genetics
- Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by the formation of fluid-filled cysts in the kidney and progressive renal failure. Other manifestations of ADPKD include the formation of cysts in other organs (liver, pancreas, and spleen), hypertension, cardiac defects, and cerebral aneurysms. The loss of function of the polycystin -1 and -2 results in the formation of epithelium-lined cysts, a process that depends on initial epithelial proliferation. cDNA microarrays powerfully monitor gene expression and have led to the discoveries of pathways regulating complex biological processes. We undertook to profile the gene expression patterns of epithelial cells derived from the cysts of ADPKD patients using the cDNA microarray technique. Candidate genes that were differently expressed in cyst tissues were identified. 19 genes were up-regulated, and 6 down-regulated. Semi-quantitative RT-PCR results were consistent with the microarray findings. To distinguish between normal and epithelial cells, we used the hierarchical method. The results obtained may provide a molecular basis for understanding the biological meaning of cytogenesis.
- Published
- 2004
- Full Text
- View/download PDF
21. Trans-heterozygous Pkd1 and Pkd2 mutations modify expression of polycystic kidney disease.
- Author
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Wu G, Tian X, Nishimura S, Markowitz GS, D'Agati V, Park JH, Yao L, Li L, Geng L, Zhao H, Edelmann W, and Somlo S
- Subjects
- Animals, Heterozygote, Humans, Membrane Proteins deficiency, Membrane Proteins metabolism, Mice, Mice, Knockout, Models, Genetic, Phenotype, Polycystic Kidney, Autosomal Dominant metabolism, Polycystic Kidney, Autosomal Dominant pathology, Proteins metabolism, TRPP Cation Channels, Membrane Proteins genetics, Mutation, Polycystic Kidney, Autosomal Dominant genetics, Proteins genetics
- Abstract
Autosomal dominant polycystic kidney disease (ADPKD) occurs by germline mutation in PKD1 or PKD2. Evidence of homozygous inactivation of either gene in human cyst lining cells as well as in mouse knockout models strongly supports a two-hit mechanism for cyst formation. Discovery of trans-heterozygous mutations in PKD1 and PKD2 in a minority of human renal cysts has led to the proposal that such mutations also can play a role in cyst formation. In the current study, we investigated the role of trans-heterozygous mutations in mouse models of polycystic kidney disease. In Pkd1(+/-), Pkd2 (+/-) and Pkd1(+/-) : Pkd2 (+/-) mice, the renal cystic lesion was mild and variable with no adverse effect on survival at 1 year. In keeping with the two-hit mechanism of cyst formation, approximately 70% of kidney cysts in Pkd2 (+/-) mice exhibited uniform loss of polycystin-2 expression. Cystic disease in trans-heterozygous Pkd1(+/-) : Pkd2 (+/-) mice, however, was notable for severity in excess of that predicted by a simple additive effect based on cyst formation in singly heterozygous mice. The data suggest a modifier role for the 'trans' polycystin gene in cystic kidney disease, and support a contribution from threshold effects to cyst formation and growth.
- Published
- 2002
- Full Text
- View/download PDF
22. Diagnostic Evaluation as a Biomarker in Patients with ADPKD
- Author
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Park, Hayne Cho, Ahn, Curie, Park, Jong Hoon, editor, and Ahn, Curie, editor
- Published
- 2016
- Full Text
- View/download PDF
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