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Tran U, Streets AJ, Smith D, Decker E, Kirschfink A, Izem L, Hassey JM, Rutland B, Valluru MK, Bräsen JH, Ott E, Epting D, Eisenberger T, Ong AC, Bergmann C, Wessely O. BICC1 Interacts with PKD1 and PKD2 to Drive Cystogenesis in ADPKD. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.08.27.608867. [PMID: 39253489 PMCID: PMC11383298 DOI: 10.1101/2024.08.27.608867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is primarily of adult-onset and caused by pathogenic variants in PKD1 or PKD2 . Yet, disease expression is highly variable and includes very early-onset PKD presentations in utero or infancy. In animal models, the RNA-binding molecule Bicc1 has been shown to play a crucial role in the pathogenesis of PKD. To study the interaction between BICC1, PKD1 and PKD2 we combined biochemical approaches, knockout studies in mice and Xenopus, genetic engineered human kidney cells as well as genetic association studies in a large ADPKD cohort. We first demonstrated that BICC1 physically binds to the proteins Polycystin-1 and -2 encoded by PKD1 and PKD2 via distinct protein domains. Furthermore, PKD was aggravated in loss-of-function studies in Xenopus and mouse models resulting in more severe disease when Bicc1 was depleted in conjunction with Pkd1 or Pkd2 . Finally, in a large human patient cohort, we identified a sibling pair with a homozygous BICC1 variant and patients with very early onset PKD (VEO-PKD) that exhibited compound heterozygosity of BICC1 in conjunction with PKD1 and PKD2 variants. Genome editing demonstrated that these BICC1 variants were hypomorphic in nature and impacted disease-relevant signaling pathways. These findings support the hypothesis that BICC1 cooperates functionally with PKD1 and PKD2 , and that BICC1 variants may aggravate PKD severity highlighting RNA metabolism as an important new concept for disease modification in ADPKD.
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Devapatla P, Jeng WY, Chiu WT, Hsieh-Li HM. The pathophysiological significance between autosomal dominant polycystic kidney disease and neutrophil gelatinase-associated lipocalin. Kidney Res Clin Pract 2025; 44:238-248. [PMID: 40083127 PMCID: PMC11985312 DOI: 10.23876/j.krcp.23.339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 03/03/2024] [Accepted: 03/22/2024] [Indexed: 03/16/2025] Open
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of polycystic kidney disease (PKD) and is a typical adult-onset multisystem disorder. It is a progressive disease characterized by the disruption of renal tubular integrity, involving the modulation of cellular proliferation and apoptosis. Most ADPKD results from a mutation in either the PKD1 or PKD2 gene encoding polycystin-1 and polycystin-2, respectively. With the inconsistent disease course of ADPKD, biomarkers that can predict the treatment efficacy and rapid progression of the disease are needed. Studies have identified neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for predicting the progression of ADPKD patients. The NGAL protein is expressed at a low level in the kidneys, which helps to regulate iron transport and participates in epithelial differentiation, inflammation, and cell proliferation. NGAL level also increases in serum and urine during renal detrimental conditions such as ischemia and acute and chronic kidney diseases. On the other hand, some studies have also demonstrated that NGAL may act as a tubulogenic factor controlling cell growth and that the upregulation of the Ngal gene hinders tubular cell proliferation, resulting in significantly reduced cyst growth in cellular and murine models of ADPKD. This review attempts to correlate ADPKD and NGAL based on available research findings to evaluate the therapeutic potential of NGAL in ADPKD.
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Affiliation(s)
- Pallavi Devapatla
- Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
| | - Wen-Yih Jeng
- University Center for Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan
| | - Wen-Tai Chiu
- Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan
| | - Hsiu Mei Hsieh-Li
- Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
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Vitulano C, Forcina G, Colosimo S, Frattolillo V, Villani AV, Marzuillo P, Miraglia Del Giudice E, Di Sessa A. A miRNA-Based Approach in Autosomal Dominant Polycystic Kidney Disease: Challenges and Insights from Adult to Pediatric Evidence. Mol Diagn Ther 2025; 29:183-193. [PMID: 39820940 DOI: 10.1007/s40291-024-00761-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/01/2024] [Indexed: 01/19/2025]
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) represents the most common inherited kidney disorder leading to kidney failure in a significant percentage of patients over time. Although previously considered as an adult disease, robust evidence demonstrated that clinical manifestations might occur during childhood and adolescence. Therefore, early identification and treatment of the disease are of cardinal importance for pediatricians to ensure the best long-term outcomes. To date, licensed treatment options are limited but promising potential therapeutic targets are emerging. Among these, an intriguing pathophysiological role for microRNAs as small molecules with a critical role in regulating gene expression has been considered possible in ADPKD. Indeed, numerous circulating microRNAs have been found to be dysregulated in ADPKD, suggesting their potential role as biomarkers and therapeutic targets. Based on this background, further detailed insights into the mechanisms of miRNAs contributing to ADPKD development might pave the way for their effective application as a targeted treatment in young patients with ADPKD. We aimed to summarize the most recent evidence in this fascinating research area, providing a comprehensive overview of the current landscape of specific microRNAs in ADPKD as a potential innovative therapeutic strategy for these young patients.
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Affiliation(s)
- Caterina Vitulano
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Via L. De Crecchio, 4, 80138, Naples, Italy
| | - Gianmario Forcina
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Via L. De Crecchio, 4, 80138, Naples, Italy
| | - Simone Colosimo
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Via L. De Crecchio, 4, 80138, Naples, Italy
| | - Vittoria Frattolillo
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Via L. De Crecchio, 4, 80138, Naples, Italy
| | - Annalisa Valentina Villani
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Via L. De Crecchio, 4, 80138, Naples, Italy
| | - Pierluigi Marzuillo
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Via L. De Crecchio, 4, 80138, Naples, Italy
| | - Emanuele Miraglia Del Giudice
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Via L. De Crecchio, 4, 80138, Naples, Italy
| | - Anna Di Sessa
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Via L. De Crecchio, 4, 80138, Naples, Italy.
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Lai S, Mastroluca D, Perrotta AM, Muscaritoli M, Lucciola S, Felli MP, Izzo P, Rotondi S, Izzo S, Tartaglione L, Belli R, Ramaccini C, Izzo L, De Intinis C, Panebianco V, Mazzaferro S. MicroRNA and renal fibrosis in autosomal dominant polycystic kidney disease: a longitudinal study. J Nephrol 2025; 38:153-162. [PMID: 38969871 PMCID: PMC11903767 DOI: 10.1007/s40620-024-01965-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 04/26/2024] [Indexed: 07/07/2024]
Abstract
BACKGROUND Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary kidney disorder that may progress to kidney failure, accounting for 5-10% of all patients with end-stage kidney disease (ESKD). Clinical data, as well as molecular genetics and advanced imaging techniques have provided surrogate prognostic biomarkers to predict rapid decline in kidney function, nonetheless enhanced tools for assessing prognosis for ADPKD are still needed. The aim of this study was to analyze specific microRNAs involved in the pathogenesis of ADPKD and in the development of renal fibrosis, evaluating their potential role as predictors of renal function loss. METHODS We evaluated kidney function by estimated glomerular filtration rate (eGFR) in 32 ADPKD patients in different stages of kidney disease at T0 and after a 24-month follow up (T1). Patients were divided into two groups: Rapid disease progression ([RP], n 15) and Non-rapid disease progression ([NRP], n 17), according to the Mayo Clinic classification criteria. At T0, ADPKD patients underwent plasma sampling for quantitative analysis of h-miR-17-5p, h-miR-21-5p and h-miR-199a-5p microRNA expression, using the quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) method and a 3 T magnetic resonance imaging (MRI), using an advanced MRI imaging protocol, for the quantification of total kidney volume (TKV), total perfusion volume (TPV) and total fibrotic volume (TFV). RESULTS The expression of h-miR17-5p was higher (p < 0.05) in ADPKD patients with rapid disease progression. h-miR-17-5p, h-miR-21-5p and h-mir-199-5p showed a positive and significant correlation with the eGFR slope (mL/min/1.73 m2/year) (p < 0.05) but not with the eGFR at both T0 and T1. Both total fibrotic volume (cm3) and height-adjusted total fibrotic volume (cm3/m) were positively and significantly correlated to h-miR 21-5p and h-miR 199-5p (p < 0.05), but not to total kidney volume (cm3) and height-adjusted total kidney volume (cm3/m). CONCLUSIONS The microRNAs we studied were associated with fibrosis and renal damage, suggesting their possible role as biomarkers able to identify ADPKD patients at high risk of disease progression regardless of the degree of kidney function, and therefore suitable for medical therapy, and may help uncovering new molecular mechanisms underlying cystogenesis.
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Affiliation(s)
- Silvia Lai
- Nephrology Unit, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
| | - Daniela Mastroluca
- Nephrology Unit, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Adolfo Marco Perrotta
- Nephrology Unit, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Maurizio Muscaritoli
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Sara Lucciola
- Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Rome, Italy
| | - Maria Pia Felli
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Paolo Izzo
- Pietro Valdoni, Department of Surgery, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Silverio Rotondi
- Nephrology Unit, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Sara Izzo
- Plastic Surgery Unit, Multidisciplinary Department of Medical-Surgical and Dental Specialties, University of Campania, "Luigi Vanvitelli", Naples, Italy
| | - Lida Tartaglione
- Nephrology Unit, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Roberta Belli
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Cesarina Ramaccini
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Luciano Izzo
- Pietro Valdoni, Department of Surgery, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Claudia De Intinis
- Pietro Valdoni, Department of Surgery, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Valeria Panebianco
- Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Rome, Italy
| | - Sandro Mazzaferro
- Nephrology Unit, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
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Knockdown of miR-214 Alleviates Renal Interstitial Fibrosis by Targeting the Regulation of the PTEN/PI3K/AKT Signalling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7553928. [PMID: 36285295 PMCID: PMC9588363 DOI: 10.1155/2022/7553928] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 09/14/2022] [Indexed: 11/22/2022]
Abstract
The microRNA-214 (miR-214) precursor is formed by the DNM3 gene on human chromosome 1q24.3, which is encoded and transcribed in the nucleus and processed into mature miR-214 in the cytoplasm. Association of miR-214 with the interstitial fibrosis of the kidney has been reported in existing research. Renal interstitial fibrosis is considered necessary during the process of various renal injuries in chronic kidney disease (CKD). One of the important mechanisms is the TGF- (transforming growth factor-) β1-stimulated epithelial interstitial transformation (EMT). The specific mechanisms of miR-214-3p in renal interstitial fibrosis and whether it participates in EMT are worthy of further investigation. In this paper, we first demonstrated modulation of the downstream PI3K/AKT axis by miR-214-3p through targeting phosphatase and tension protein homologues (PTEN), indicating the miRNA's participation in unilateral ureteral obstruction (UUO) nephropathy and TGF-β1-induced EMT. We overexpressed or silenced miR-214-3p and PTEN for probing into the correlation of miR-214-3p with PTEN and the downstream PI3K/AKT signalling pathways. According to the results of the study, miR-214-3p overexpression silenced PTEN, activated the PI3K/AKT signalling pathway, and exacerbated EMT induced by TGF-β1, while miR-214-3p knockdown had the opposite effect. In miR-214-3p knockdown mice, the expression of PTEN was increased, the PI3K/AKT signalling pathway was inhibited, and fibrosis was alleviated. In conclusion, miR-214-3p regulates the EMT of renal tubular cells induced by TGF-β1 by targeting PTEN and regulating the PI3K/AKT signalling pathway. Furthermore, miR-214-3p knockdown can reduce renal interstitial fibrosis through the PTEN/PI3K/AKT pathway.
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Su CT, See DHW, Huang JW. Lipid-Based Nanocarriers in Renal RNA Therapy. Biomedicines 2022; 10:283. [PMID: 35203492 PMCID: PMC8869454 DOI: 10.3390/biomedicines10020283] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 01/22/2022] [Accepted: 01/24/2022] [Indexed: 01/27/2023] Open
Abstract
Kidney disease is a multifactorial problem, with a growing prevalence and an increasing global burden. With the latest worldwide data suggesting that chronic kidney disease (CKD) is the 12th leading cause of death, it is no surprise that CKD remains a public health problem that requires urgent attention. Multiple factors contribute to kidney disease, each with its own pathophysiology and pathogenesis. Furthermore, microRNAs (miRNAs) have been linked to several types of kidney diseases. As dysregulation of miRNAs is often seen in some diseases, there is potential in the exploitation of this for therapeutic applications. In addition, uptake of interference RNA has been shown to be rapid in kidneys making them a good candidate for RNA therapy. The latest advancements in RNA therapy and lipid-based nanocarriers have enhanced the effectiveness and efficiency of RNA-related drugs, thereby making RNA therapy a viable treatment option for renal disease. This is especially useful for renal diseases, for which a suitable treatment is not yet available. Moreover, the high adaptability of RNA therapy combined with the low risk of lipid-based nanocarriers make for an attractive treatment choice. Currently, there are only a small number of RNA-based drugs related to renal parenchymal disease, most of which are in different stages of clinical trials. We propose the use of miRNAs or short interfering RNAs coupled with a lipid-based nanocarrier as a delivery vehicle for managing renal disease.
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Affiliation(s)
- Chi-Ting Su
- Department of Medicine, National Taiwan University Cancer Centre, Taipei 10672, Taiwan; (C.-T.S.); (D.H.W.S.)
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Renal Division, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Douliu 640, Taiwan
| | - Daniel H. W. See
- Department of Medicine, National Taiwan University Cancer Centre, Taipei 10672, Taiwan; (C.-T.S.); (D.H.W.S.)
| | - Jenq-Wen Huang
- Renal Division, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Douliu 640, Taiwan
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Pagliarini R, Podrini C. Metabolic Reprogramming and Reconstruction: Integration of Experimental and Computational Studies to Set the Path Forward in ADPKD. Front Med (Lausanne) 2021; 8:740087. [PMID: 34901057 PMCID: PMC8652061 DOI: 10.3389/fmed.2021.740087] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 10/25/2021] [Indexed: 12/17/2022] Open
Abstract
Metabolic reprogramming is a key feature of Autosomal Dominant Polycystic Kidney Disease (ADPKD) characterized by changes in cellular pathways occurring in response to the pathological cell conditions. In ADPKD, a broad range of dysregulated pathways have been found. The studies supporting alterations in cell metabolism have shown that the metabolic preference for abnormal cystic growth is to utilize aerobic glycolysis, increasing glutamine uptake and reducing oxidative phosphorylation, consequently resulting in ADPKD cells shifting their energy to alternative energetic pathways. The mechanism behind the role of the polycystin proteins and how it leads to disease remains unclear, despite the identification of numerous signaling pathways. The integration of computational data analysis that accompanies experimental findings was pivotal in the identification of metabolic reprogramming in ADPKD. Here, we summarize the important results and argue that their exploitation may give further insights into the regulative mechanisms driving metabolic reprogramming in ADPKD. The aim of this review is to provide a comprehensive overview on metabolic focused studies and potential targets for treatment, and to propose that computational approaches could be instrumental in advancing this field of research.
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Affiliation(s)
- Roberto Pagliarini
- Molecular Basis of Cystic Kidney Disorders Unit, Division of Genetics and Cell Biology, IRCCS-San Raffaele Scientific Institute, Milan, Italy
| | - Christine Podrini
- Molecular Basis of Cystic Kidney Disorders Unit, Division of Genetics and Cell Biology, IRCCS-San Raffaele Scientific Institute, Milan, Italy
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Cordido A, Nuñez-Gonzalez L, Martinez-Moreno JM, Lamas-Gonzalez O, Rodriguez-Osorio L, Perez-Gomez MV, Martin-Sanchez D, Outeda P, Chiaravalli M, Watnick T, Boletta A, Diaz C, Carracedo A, Sanz AB, Ortiz A, Garcia-Gonzalez MA. TWEAK Signaling Pathway Blockade Slows Cyst Growth and Disease Progression in Autosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol 2021; 32:1913-1932. [PMID: 34155062 PMCID: PMC8455272 DOI: 10.1681/asn.2020071094] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 03/06/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND In autosomal dominant polycystic kidney disease (ADPKD), cyst development and enlargement lead to ESKD. Macrophage recruitment and interstitial inflammation promote cyst growth. TWEAK is a TNF superfamily (TNFSF) cytokine that regulates inflammatory responses, cell proliferation, and cell death, and its receptor Fn14 (TNFRSF12a) is expressed in macrophage and nephron epithelia. METHODS To evaluate the role of the TWEAK signaling pathway in cystic disease, we evaluated Fn14 expression in human and in an orthologous murine model of ADPKD. We also explored the cystic response to TWEAK signaling pathway activation and inhibition by peritoneal injection. RESULTS Meta-analysis of published animal-model data of cystic disease reveals mRNA upregulation of several components of the TWEAK signaling pathway. We also observed that TWEAK and Fn14 were overexpressed in mouse ADPKD kidney cysts, and TWEAK was significantly high in urine and cystic fluid from patients with ADPKD. TWEAK administration induced cystogenesis and increased cystic growth, worsening the phenotype in a murine ADPKD model. Anti-TWEAK antibodies significantly slowed the progression of ADPKD, preserved renal function, and improved survival. Furthermore, the anti-TWEAK cystogenesis reduction is related to decreased cell proliferation-related MAPK signaling, decreased NF-κB pathway activation, a slight reduction of fibrosis and apoptosis, and an indirect decrease in macrophage recruitment. CONCLUSIONS This study identifies the TWEAK signaling pathway as a new disease mechanism involved in cystogenesis and cystic growth and may lead to a new therapeutic approach in ADPKD.
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Affiliation(s)
- Adrian Cordido
- Group of Genetics and Developmental Biology of Renal Diseases, Nephrology Laboratory (N°11), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,Genomic Medicine Group, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain
| | - Laura Nuñez-Gonzalez
- Group of Genetics and Developmental Biology of Renal Diseases, Nephrology Laboratory (N°11), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,Genomic Medicine Group, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain
| | - Julio M. Martinez-Moreno
- Department of Nephrology and Hypertension, Jiménez Díaz Foundation (Health Research Institute and Autonomous University of Madrid), Madrid, Spain
| | - Olaya Lamas-Gonzalez
- Group of Genetics and Developmental Biology of Renal Diseases, Nephrology Laboratory (N°11), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain
| | - Laura Rodriguez-Osorio
- RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain,Department of Nephrology and Hypertension, Jiménez Díaz Foundation (Health Research Institute and Autonomous University of Madrid), Madrid, Spain
| | - Maria Vanessa Perez-Gomez
- RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain,Department of Nephrology and Hypertension, Jiménez Díaz Foundation (Health Research Institute and Autonomous University of Madrid), Madrid, Spain
| | - Diego Martin-Sanchez
- RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain,Department of Nephrology and Hypertension, Jiménez Díaz Foundation (Health Research Institute and Autonomous University of Madrid), Madrid, Spain
| | - Patricia Outeda
- Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Marco Chiaravalli
- Division of Genetics and Cell Biology, Molecular Basis of Cystic Kidney Disorders Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)–San Raffaele Scientific Institute, Milan, Italy
| | - Terry Watnick
- Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | | | - Candido Diaz
- Group of Genetics and Developmental Biology of Renal Diseases, Nephrology Laboratory (N°11), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,Nephrology Service, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain
| | - Angel Carracedo
- Genomic Medicine Group, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,Galician Public Foundation of Genomic Medicine, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,Center in Network of Rare Diseases (CIBERER), University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Ana B. Sanz
- RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain,Department of Nephrology and Hypertension, Jiménez Díaz Foundation (Health Research Institute and Autonomous University of Madrid), Madrid, Spain
| | - Alberto Ortiz
- RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain,Department of Nephrology and Hypertension, Jiménez Díaz Foundation (Health Research Institute and Autonomous University of Madrid), Madrid, Spain
| | - Miguel A. Garcia-Gonzalez
- Group of Genetics and Developmental Biology of Renal Diseases, Nephrology Laboratory (N°11), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,Genomic Medicine Group, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain,Galician Public Foundation of Genomic Medicine, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain
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9
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Non-Coding RNAs in Hereditary Kidney Disorders. Int J Mol Sci 2021; 22:ijms22063014. [PMID: 33809516 PMCID: PMC7998154 DOI: 10.3390/ijms22063014] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/10/2021] [Accepted: 03/12/2021] [Indexed: 12/17/2022] Open
Abstract
Single-gene defects have been revealed to be the etiologies of many kidney diseases with the recent advances in molecular genetics. Autosomal dominant polycystic kidney disease (ADPKD), as one of the most common inherited kidney diseases, is caused by mutations of PKD1 or PKD2 gene. Due to the complexity of pathophysiology of cyst formation and progression, limited therapeutic options are available. The roles of noncoding RNAs in development and disease have gained widespread attention in recent years. In particular, microRNAs in promoting PKD progression have been highlighted. The dysregulated microRNAs modulate cyst growth through suppressing the expression of PKD genes and regulating cystic renal epithelial cell proliferation, mitochondrial metabolism, apoptosis and autophagy. The antagonists of microRNAs have emerged as potential therapeutic drugs for the treatment of ADPKD. In addition, studies have also focused on microRNAs as potential biomarkers for ADPKD and other common hereditary kidney diseases, including HNF1β-associated kidney disease, Alport syndrome, congenital abnormalities of the kidney and urinary tract (CAKUT), von Hippel-Lindau (VHL) disease, and Fabry disease. This review assembles the current understanding of the non-coding RNAs, including microRNAs and long noncoding RNAs, in polycystic kidney disease and these common monogenic kidney diseases.
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10
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Li Y, Gao J, Yang X, Li T, Yang B, Aili A. Combination of curcumin and ginkgolide B inhibits cystogenesis by regulating multiple signaling pathways. Mol Med Rep 2021; 23:195. [PMID: 33495815 PMCID: PMC7821343 DOI: 10.3892/mmr.2021.11834] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 11/20/2020] [Indexed: 12/05/2022] Open
Abstract
Autosomal dominant polycystic kidney disease (ADPKD), a common disease with a high incidence ratio of between 1/400 and 1/1,000 individuals, often results in kidney failure and even mortality. However, there are relatively few effective treatments available, and treatment is limited to lifelong hemodialysis or kidney transplant. Our previous studies have reported that curcumin (Cur) and ginkgolide B (GB) inhibited cystogenesis by regulating the Ras/ERK MAPK signaling pathway. In the present study, it was hypothesized that Cur and GB may have a synergistic effect on the inhibition of cystogenesis, and their synergistic effect may be the result of regulation of multiple signaling pathways. To assess this hypothesis, an in vitro Madin‑Darby canine kidney (MDCK) cyst model and an in vivo kidney‑specific polycystin 1 transient receptor potential channel interacting (Pkd1) knockout mouse model were established to observe the effects of the combination of Cur and GB. The cysts exposed to Cur, GB and Cur combined with GB became small thick‑walled cysts, small thin‑walled cysts and round shaped cell colonies, respectively. The combination of Cur and GB was more effective compared with either treatment alone in inhibiting cystogenesis. Additionally, to the best of our knowledge, the present study was the first to demonstrate the synergistic effect of Cur and GB on the inhibition of cystogenesis in Pkd1 knockout mice. Cur may have mediated its anti‑cyst effects by blocking EGFR/ERK1/2, JNK and PI3K/mTOR signaling pathways, while GB may have inhibited cystogenesis via the downregulation of the EGFR/ERK1/2, JNK and p38 signaling pathways. These results provide a proof‑of‑concept for application of the combination of Cur and GB in inhibiting cystogenesis in ADPKD.
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Affiliation(s)
- Yousong Li
- Department of Traditional Chinese Medicine, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, P.R. China
| | - Jinsheng Gao
- Ping An Healthcare and Technology Company Limited (‘Ping an’), Shanghai 200120, P.R. China
| | - Xi Yang
- Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| | - Tao Li
- Ping An Healthcare and Technology Company Limited (‘Ping an’), Shanghai 200120, P.R. China
| | - Baoxue Yang
- Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100083, P.R. China
| | - Aixingzi Aili
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, P.R. China
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11
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Gbotosho OT, Kapetanaki MG, Kato GJ. The Worst Things in Life are Free: The Role of Free Heme in Sickle Cell Disease. Front Immunol 2021; 11:561917. [PMID: 33584641 PMCID: PMC7873693 DOI: 10.3389/fimmu.2020.561917] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 12/04/2020] [Indexed: 12/15/2022] Open
Abstract
Hemolysis is a pathological feature of several diseases of diverse etiology such as hereditary anemias, malaria, and sepsis. A major complication of hemolysis involves the release of large quantities of hemoglobin into the blood circulation and the subsequent generation of harmful metabolites like labile heme. Protective mechanisms like haptoglobin-hemoglobin and hemopexin-heme binding, and heme oxygenase-1 enzymatic degradation of heme limit the toxicity of the hemolysis-related molecules. The capacity of these protective systems is exceeded in hemolytic diseases, resulting in high residual levels of hemolysis products in the circulation, which pose a great oxidative and proinflammatory risk. Sickle cell disease (SCD) features a prominent hemolytic anemia which impacts the phenotypic variability and disease severity. Not only is circulating heme a potent oxidative molecule, but it can act as an erythrocytic danger-associated molecular pattern (eDAMP) molecule which contributes to a proinflammatory state, promoting sickle complications such as vaso-occlusion and acute lung injury. Exposure to extracellular heme in SCD can also augment the expression of placental growth factor (PlGF) and interleukin-6 (IL-6), with important consequences to enthothelin-1 (ET-1) secretion and pulmonary hypertension, and potentially the development of renal and cardiac dysfunction. This review focuses on heme-induced mechanisms that are implicated in disease pathways, mainly in SCD. A special emphasis is given to heme-induced PlGF and IL-6 related mechanisms and their role in SCD disease progression.
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Affiliation(s)
- Oluwabukola T. Gbotosho
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Maria G. Kapetanaki
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Gregory J. Kato
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
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12
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Fragiadaki M, Macleod FM, Ong ACM. The Controversial Role of Fibrosis in Autosomal Dominant Polycystic Kidney Disease. Int J Mol Sci 2020; 21:ijms21238936. [PMID: 33255651 PMCID: PMC7728143 DOI: 10.3390/ijms21238936] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 11/19/2020] [Accepted: 11/23/2020] [Indexed: 02/06/2023] Open
Abstract
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by the progressive growth of cysts but it is also accompanied by diffuse tissue scarring or fibrosis. A number of recent studies have been published in this area, yet the role of fibrosis in ADPKD remains controversial. Here, we will discuss the stages of fibrosis progression in ADPKD, and how these compare with other common kidney diseases. We will also provide a detailed overview of some key mechanistic pathways to fibrosis in the polycystic kidney. Specifically, the role of the 'chronic hypoxia hypothesis', persistent inflammation, Transforming Growth Factor beta (TGFβ), Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) and microRNAs will be examined. Evidence for and against a pathogenic role of extracellular matrix during ADPKD disease progression will be provided.
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13
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GENEŞ D, PEKKOLAY Z, BEYAZ C, KILINÇ F, TUZCU AK. Is HbA1c Misleading and 90-Minute Glucose Tolerance Test a Better Indicator in the Diagnosis of Diabetes Mellitus? DICLE MEDICAL JOURNAL 2020. [DOI: 10.5798/dicletip.706051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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14
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YILMAZ K, GUNDUZ Z, KUTUK MS, DUSUNSEL R, DURSUN İ, YEL S. The Relationship Between MicroRNAs And Congenital Kidney Anomalies. DICLE MEDICAL JOURNAL 2020. [DOI: 10.5798/dicletip.706048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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15
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Magayr TA, Song X, Streets AJ, Vergoz L, Chang L, Valluru MK, Yap HL, Lannoy M, Haghighi A, Simms RJ, Tam FWK, Pei Y, Ong ACM. Global microRNA profiling in human urinary exosomes reveals novel disease biomarkers and cellular pathways for autosomal dominant polycystic kidney disease. Kidney Int 2020; 98:420-435. [PMID: 32622528 DOI: 10.1016/j.kint.2020.02.008] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 01/14/2020] [Accepted: 02/06/2020] [Indexed: 12/17/2022]
Abstract
MicroRNAs (miRNAs) play an important role in regulating gene expression in health and disease but their role in modifying disease expression in Autosomal Dominant Polycystic Kidney Disease (ADPKD) remains uncertain. Here, we profiled human urinary exosome miRNA by global small RNA-sequencing in an initial discovery cohort of seven patients with ADPKD with early disease (eGFR over 60ml/min/1.73m2), nine with late disease (eGFR under 60ml/min/1.73m2), and compared their differential expression with six age and sex matched healthy controls. Two kidney-enriched candidate miRNA families were identified (miR-192/miR-194-2 and miR-30) and selected for confirmatory testing in a 60 patient validation cohort by quantitative polymerase chain reaction. We confirmed that miR-192-5p, miR-194-5p, miR-30a-5p, miR-30d-5p and miR-30e-5p were significantly downregulated in patient urine exosomes, in murine Pkd1 cystic kidneys and in human PKD1 cystic kidney tissue. All five miRNAs showed significant correlations with baseline eGFR and ultrasound-determined mean kidney length and improved the diagnostic performance (area under the curve) of mean kidney length for the rate of disease progression. Finally, inverse correlations of these two miRNA families with increased expression in their predicted target genes in patient PKD1 cystic tissue identified dysregulated pathways and transcriptional networks including novel interactions between miR-194-5p and two potentially relevant candidate genes, PIK3R1 and ANO1. Thus, our results identify a subset of urinary exosomal miRNAs that could serve as novel biomarkers of disease progression and suggest new therapeutic targets in ADPKD.
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Affiliation(s)
- Tajdida A Magayr
- Kidney Genetics Group, Academic Nephrology Unit, University of Sheffield Medical School, Sheffield, UK
| | - Xuewen Song
- Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Andrew J Streets
- Kidney Genetics Group, Academic Nephrology Unit, University of Sheffield Medical School, Sheffield, UK
| | - Laura Vergoz
- Kidney Genetics Group, Academic Nephrology Unit, University of Sheffield Medical School, Sheffield, UK
| | - Lijun Chang
- Kidney Genetics Group, Academic Nephrology Unit, University of Sheffield Medical School, Sheffield, UK
| | - Manoj K Valluru
- Kidney Genetics Group, Academic Nephrology Unit, University of Sheffield Medical School, Sheffield, UK
| | - Hsiu L Yap
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, Hammersmith Hospital, London, UK
| | - Morgane Lannoy
- Kidney Genetics Group, Academic Nephrology Unit, University of Sheffield Medical School, Sheffield, UK
| | - Amirreza Haghighi
- Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Roslyn J Simms
- Kidney Genetics Group, Academic Nephrology Unit, University of Sheffield Medical School, Sheffield, UK
| | - Frederick W K Tam
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, Hammersmith Hospital, London, UK
| | - York Pei
- Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada.
| | - Albert C M Ong
- Kidney Genetics Group, Academic Nephrology Unit, University of Sheffield Medical School, Sheffield, UK.
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16
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Yan Z, Zang B, Gong X, Ren J, Wang R. MiR-214-3p exacerbates kidney damages and inflammation induced by hyperlipidemic pancreatitis complicated with acute renal injury. Life Sci 2020; 241:117118. [PMID: 31790686 DOI: 10.1016/j.lfs.2019.117118] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 11/15/2019] [Accepted: 11/27/2019] [Indexed: 12/11/2022]
Abstract
AIMS Acute pancreatitis (AP) is usually complicated with multiple organ insufficiency, including renal injury. Hyperlipidemia is regarded as a risk factor to induce AP. High-fat diet-induced hyperlipidemic pancreatitis (HP) increased nowadays and showed more severe symptoms and complications than other AP. However, detailed mechanisms or mediators involved in HP complicated with acute renal injury were less studied. Here, we aimed to study how miR-214 expresses in the HP and whether miR-214 has functions to regulate pathological kidney damages induced by HP. MAIN METHODS Sprague-Dawley rats were adopted to establish HP model complicated with acute renal injury through long-term high-fat diet and sodium taurocholic injection. Models were injected with LV-rno-miR-214-3p or LV-anti-rno-miR-214-3p to exogenously regulate miR-214-3p to study its impacts on HP via a series of molecular and histological experiments. KEY FINDINGS MiR-214-3p was found to be up-regulated in the kidney, pancreas and serum of HP rats and also could intensify the pathological alterations, kidney and pancreas damages and fibrosis induced by HP. Inflammatory response in HP was enhanced when miR-214-3p was overexpressed. Besides, miR-214-3p up-regulation was showed to inhibit PTEN expression but increased P-Akt levels in the HP kidney, which might be a possible mechanism to induce severe symptoms of pancreatitis. Knockdown of miR-214-3p showed opposite effects. SIGNIFICANCE MiR-214-3p is indicated to exacerbate the tissue damages and inflammatory response caused by HP complicated with acute renal injury, which may provide a novel therapeutic perspective targeting miR-214-3p to treat HP with acute renal injury.
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Affiliation(s)
- Zhaopeng Yan
- Department of General Surgery, Shengjing Hospital, China Medical University, Shenyang, Liaoning, China
| | - Bin Zang
- Department of Critical Care Medicine, Shengjing Hospital, China Medical University, Shenyang, Liaoning, China
| | - Xiaoying Gong
- Department of Critical Care Medicine, Shengjing Hospital, China Medical University, Shenyang, Liaoning, China
| | - Jiangyue Ren
- Department of Critical Care Medicine, Shengjing Hospital, China Medical University, Shenyang, Liaoning, China
| | - Rui Wang
- Department of Critical Care Medicine, Shengjing Hospital, China Medical University, Shenyang, Liaoning, China.
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17
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Muñoz JJ, Anauate AC, Amaral AG, Ferreira FM, Meca R, Ormanji MS, Boim MA, Onuchic LF, Heilberg IP. Identification of housekeeping genes for microRNA expression analysis in kidney tissues of Pkd1 deficient mouse models. Sci Rep 2020; 10:231. [PMID: 31937827 PMCID: PMC6959247 DOI: 10.1038/s41598-019-57112-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 12/21/2019] [Indexed: 12/11/2022] Open
Abstract
Polycystic kidney disease is a complex clinical entity which comprises a group of genetic diseases that leads to renal cyst development. We evaluated the most suitable housekeeping genes for microRNA expression by RT-qPCR analyses of kidney tissues in Pkd1-deficient mouse models from a panel of five candidates genes (miR-20a, miR-25, miR-26a, miR-191 and U6) and 3 target genes (miR-17, miR-21 and let-7a) using samples from kidneys of cystic mice (Pkd1flox/flox:Nestincre, CY), non-cystic controls (Pkd1flox/flox, NC), Pkd1-haploinsufficient (Pkd1+/−, HT), wild-type controls (Pkd1+/+, WT), severely cystic mice (Pkd1V/V, SC), wild-type controls (CO). The stability of the candidate genes was investigated using NormFinder, GeNorm, BestKeeper, DataAssist, and RefFinder software packages and the comparative ΔCt method. The analyses identified miR-26a as the most stable housekeeping gene for all kidney samples, miR-20a for CY and NC, miR-20a and miR-26a for HT and WT, and miR-25 and miR-26a for SC and CO. Expression of miR-21 was upregulated in SC compared to CO and trends of miR-21 upregulation and let-7a downregulation in CY and HT compared to its control kidneys, when normalized by different combinations of miR-20a, miR-25 and miR-26a. Our findings established miR-20a, miR-25, and miR-26a as the best housekeeping genes for miRNA expression analyses by RT-qPCR in kidney tissues of Pkd1-deficient mouse models.
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Affiliation(s)
- J J Muñoz
- Nephrology Division, Department of Medicine, Universidade Federal de São Paulo, São Paulo, Brazil
| | - A C Anauate
- Nephrology Division, Department of Medicine, Universidade Federal de São Paulo, São Paulo, Brazil
| | - A G Amaral
- Divisions of Molecular Medicine and Nephrology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - F M Ferreira
- Laboratory of Immunology, Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil
| | - R Meca
- Nephrology Division, Department of Medicine, Universidade Federal de São Paulo, São Paulo, Brazil
| | - M S Ormanji
- Nephrology Division, Department of Medicine, Universidade Federal de São Paulo, São Paulo, Brazil
| | - M A Boim
- Nephrology Division, Department of Medicine, Universidade Federal de São Paulo, São Paulo, Brazil
| | - L F Onuchic
- Divisions of Molecular Medicine and Nephrology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - I P Heilberg
- Nephrology Division, Department of Medicine, Universidade Federal de São Paulo, São Paulo, Brazil.
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18
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Park JH, Kim OH, Kim KH, Hong HE, Seo H, Choi HJ, Ahn J, Lee TY, Kim SJ. Isolation of Secretome with Enhanced Antifibrotic Properties from miR-214-Transfected Adipose-Derived Stem Cells. J Korean Med Sci 2019; 34:e273. [PMID: 31760709 PMCID: PMC6875435 DOI: 10.3346/jkms.2019.34.e273] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 09/23/2019] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Secretome refers to the total set of molecules secreted or surface-shed by stem cells. The limitations of stem cell research have led numerous investigators to turn their attention to the use of secretome instead of stem cells. In this study, we intended to reinforce antifibrotic properties of the secretome released from adipose-derived stem cells (ASCs) transfected with miR-214. METHODS We generated miR-214-transfected ASCs, and extracted the secretome (miR214-secretome) from conditioned media of the transfected ASCs through a series of ultrafiltrations. Subsequently, we intravenously injected the miR-214-secretome into mice with liver fibrosis, and determined the effects of miR-214-secretome on liver fibrosis. RESULTS Compared with that by naïve secretome, liver fibrosis was ameliorated by intravenous infusion of miR-214-secretome into mice with liver fibrosis, which was demonstrated by significantly lower expression of fibrosis-related markers (alpha-smooth muscle actin, transforming growth factor-β, and metalloproteinases-2) in the livers as well as lower fibrotic scores in the special stained livers compared with naïve secretome. The infusion of miR-214-secretome also led to lesser local and systemic inflammation, higher expression of an antioxidant enzyme (superoxide dismutase), and higher liver proliferative and synthetic function. CONCLUSION MicroRNA-214 transfection stimulates ASCs to release the secretome with higher antifibrotic and anti-inflammatory properties. miR-214-secretome is thus expected to be one of the prominent ways of overcoming liver fibrosis, if further studies consistently validate its safety and efficiency.
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Affiliation(s)
- Jung Hyun Park
- Department of Surgery, Eunpyeong St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Ok Hee Kim
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Kee Hwan Kim
- Department of Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Ha Eun Hong
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Haeyeon Seo
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Ho Joong Choi
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Joseph Ahn
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Tae Yun Lee
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Say June Kim
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul, Korea.
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19
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Tsai YC, Teng IL, Jiang ST, Lee YC, Chiou YY, Cheng FY. Safe Nanocomposite-Mediated Efficient Delivery of MicroRNA Plasmids for Autosomal Dominant Polycystic Kidney Disease (ADPKD) Therapy. Adv Healthc Mater 2019; 8:e1801358. [PMID: 30672150 DOI: 10.1002/adhm.201801358] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 01/03/2019] [Indexed: 12/14/2022]
Abstract
There is currently no cure for gene mutation-caused autosomal dominant polycystic kidney disease (ADPKD). Over half of patients with ADPKD eventually develop kidney failure, requiring dialysis or kidney transplantation. Current treatment modalities for ADPKD focus on reducing morbidity and mortality from renal and extrarenal complications of the disease. MicroRNA has been shown to be useful in treating ADPKD. This study combines anti-miRNA plasmids and iron oxide/alginate nanoparticles for conjugation with antikidney antibodies. These nanocomposites can specifically target renal tubular cells, providing a potential treatment for ADPKD. Magnetic resonance imaging and in vivo imaging system results show effective targeting of renal cells. Anti-miRNA plasmids released from the nanocomposites inhibit cell proliferation and cyst formation in the PKD cellular and animal models. The results suggest the novel combination of the anti-miRNA plasmids and nanomaterials provides potential clinical implications for ADPKD treatment.
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Affiliation(s)
- Yen-Chang Tsai
- Institute of Clinical Medicine; Medical College; National Cheng Kung University; Tainan 701 Taiwan
| | - I-Ling Teng
- Division of Pediatric Nephrology; Department of Pediatrics; National Cheng Kung University Hospital; Tainan 704 Taiwan
| | - Si-Tse Jiang
- National Laboratory Animal Center; National Applied Research Laboratories; Tainan 741 Taiwan
| | - Yi-Che Lee
- Division of Nephrology; Department of Internal Medicine; E-DA Hospital; I-Shou University; Kaohsiung 824 Taiwan
| | - Yuan-Yow Chiou
- Institute of Clinical Medicine; Medical College; National Cheng Kung University; Tainan 701 Taiwan
- Division of Pediatric Nephrology; Department of Pediatrics; National Cheng Kung University Hospital; Tainan 704 Taiwan
- Department of Pediatrics; College of Medicine; National Cheng Kung University; Tainan 704 Taiwan
| | - Fong-Yu Cheng
- Department of Chemistry; Chinese Culture University; 55, Hwa-Kang Road, Yang-Ming-Shan Taipei 11114 Taiwan
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20
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Weimbs T, Shillingford JM, Torres J, Kruger SL, Bourgeois BC. Emerging targeted strategies for the treatment of autosomal dominant polycystic kidney disease. Clin Kidney J 2018; 11:i27-i38. [PMID: 30581563 PMCID: PMC6295603 DOI: 10.1093/ckj/sfy089] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Accepted: 08/27/2018] [Indexed: 12/25/2022] Open
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is a widespread genetic disease that leads to renal failure in the majority of patients. The very first pharmacological treatment, tolvaptan, received Food and Drug Administration approval in 2018 after previous approval in Europe and other countries. However, tolvaptan is moderately effective and may negatively impact a patient's quality of life due to potentially significant side effects. Additional and improved therapies are still urgently needed, and several clinical trials are underway, which are discussed in the companion paper Müller and Benzing (Management of autosomal-dominant polycystic kidney disease-state-of-the-art) Clin Kidney J 2018; 11: i2-i13. Here, we discuss new therapeutic avenues that are currently being investigated at the preclinical stage. We focus on mammalian target of rapamycin and dual kinase inhibitors, compounds that target inflammation and histone deacetylases, RNA-targeted therapeutic strategies, glucosylceramide synthase inhibitors, compounds that affect the metabolism of renal cysts and dietary restriction. We discuss tissue targeting to renal cysts of small molecules via the folate receptor, and of monoclonal antibodies via the polymeric immunoglobulin receptor. A general problem with potential pharmacological approaches is that the many molecular targets that have been implicated in ADPKD are all widely expressed and carry out important functions in many organs and tissues. Because ADPKD is a slowly progressing, chronic disease, it is likely that any therapy will have to continue over years and decades. Therefore, systemically distributed drugs are likely to lead to potentially prohibitive extra-renal side effects during extended treatment. Tissue targeting to renal cysts of such drugs is one potential way around this problem. The use of dietary, instead of pharmacological, interventions is another.
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Affiliation(s)
- Thomas Weimbs
- Department of Molecular, Cellular, and Developmental Biology; and Neuroscience Research Institute, University of California, Santa Barbara, CA, USA
| | - Jonathan M Shillingford
- Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA
| | - Jacob Torres
- Department of Molecular, Cellular, and Developmental Biology; and Neuroscience Research Institute, University of California, Santa Barbara, CA, USA
| | - Samantha L Kruger
- Department of Molecular, Cellular, and Developmental Biology; and Neuroscience Research Institute, University of California, Santa Barbara, CA, USA
| | - Bryan C Bourgeois
- Department of Molecular, Cellular, and Developmental Biology; and Neuroscience Research Institute, University of California, Santa Barbara, CA, USA
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21
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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, Park JH. Impact of miR-192 and miR-194 on cyst enlargement through EMT in autosomal dominant polycystic kidney disease. FASEB J 2018; 33:2870-2884. [PMID: 30332302 DOI: 10.1096/fj.201800563rr] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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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Affiliation(s)
- Do Yeon Kim
- Department of Biological Sciences, Sookmyung Women's University, Seoul, South Korea.,Research Institute of Women's Health, Sookmyung Women's University, Seoul, South Korea
| | - Yu Mi Woo
- Department of Biological Sciences, Sookmyung Women's University, Seoul, South Korea.,Research Institute of Women's Health, Sookmyung Women's University, Seoul, South Korea
| | - Sunyoung Lee
- Department of Biological Sciences, Sookmyung Women's University, Seoul, South Korea.,Research Institute of Women's Health, Sookmyung Women's University, Seoul, South Korea
| | - Sumin Oh
- Department of Biological Sciences, Sookmyung Women's University, Seoul, South Korea.,Research Institute of Women's Health, Sookmyung Women's University, Seoul, South Korea
| | - Yubin Shin
- Department of Biological Sciences, Sookmyung Women's University, Seoul, South Korea.,Research Institute of Women's Health, Sookmyung Women's University, Seoul, South Korea
| | - Jeong-Oh Shin
- Department of Anatomy, Yonsei University College of Medicine, Seoul, South Korea; and
| | - Eun Young Park
- Department of Biological Sciences, Sookmyung Women's University, Seoul, South Korea.,Research Institute of Women's Health, Sookmyung Women's University, Seoul, South Korea
| | - Je Yeong Ko
- Department of Biological Sciences, Sookmyung Women's University, Seoul, South Korea.,Research Institute of Women's Health, Sookmyung Women's University, Seoul, South Korea
| | - Eun Ji Lee
- Department of Biological Sciences, Sookmyung Women's University, Seoul, South Korea.,Research Institute of Women's Health, Sookmyung Women's University, Seoul, South Korea
| | - Jinwoong Bok
- Department of Anatomy, Yonsei University College of Medicine, Seoul, South Korea; and.,Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, South Korea
| | - Kyung Hyun Yoo
- Department of Biological Sciences, Sookmyung Women's University, Seoul, South Korea.,Research Institute of Women's Health, Sookmyung Women's University, Seoul, South Korea
| | - Jong Hoon Park
- Department of Biological Sciences, Sookmyung Women's University, Seoul, South Korea.,Research Institute of Women's Health, Sookmyung Women's University, Seoul, South Korea
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22
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Role of MicroRNAs in Renal Parenchymal Diseases-A New Dimension. Int J Mol Sci 2018; 19:ijms19061797. [PMID: 29914215 PMCID: PMC6032378 DOI: 10.3390/ijms19061797] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Revised: 06/07/2018] [Accepted: 06/08/2018] [Indexed: 11/18/2022] Open
Abstract
Since their discovery in 1993, numerous microRNAs (miRNAs) have been identified in humans and other eukaryotic organisms, and their role as key regulators of gene expression is still being elucidated. It is now known that miRNAs not only play a central role in the processes that ensure normal development and physiology, but they are often dysregulated in various diseases. In this review, we present an overview of the role of miRNAs in normal renal development and physiology, in maladaptive renal repair after injury, and in the pathogenesis of renal parenchymal diseases. In addition, we describe methods used for their detection and their potential as therapeutic targets. Continued research on renal miRNAs will undoubtedly improve our understanding of diseases affecting the kidneys and may also lead to new therapeutic agents.
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23
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Shyamasundar S, Ong C, Yung LYL, Dheen ST, Bay BH. miR-128 Regulates Genes Associated with Inflammation and Fibrosis of Rat Kidney Cells In Vitro. Anat Rec (Hoboken) 2018; 301:913-921. [PMID: 29278451 DOI: 10.1002/ar.23763] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Revised: 05/26/2017] [Accepted: 09/19/2017] [Indexed: 12/17/2022]
Abstract
microRNAs (miRNAs) regulate diverse cellular functions and signaling pathways via inhibiting the expression of their target genes. Given that miR-128 mediates mitogen-activated protein kinase signaling and production of reactive oxygen species and pro-inflammatory chemokines in various types of cells and tissues, and that miR-128 is differentially expressed in aged and diseased kidneys, we hypothesized that miR-128 may play key roles in kidney inflammation. Hence, in this study, we evaluated the biological effects of miR-128 in normal rat kidney (NRK) cells in vitro. Our results revealed that overexpression of miR-128 enhanced expression of genes associated with inflammation, pro-inflammatory cytokines and fibrosis in NRK cells. The recent reports showing that expression of miR-128 is increased in liver and lung fibrosis, together with the findings in this study, suggest that miR-128 may be a pro-fibrotic miRNA that regulates fibrosis in various tissues. Anat Rec, 301:913-921, 2018. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Sukanya Shyamasundar
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore
| | - Cynthia Ong
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore
| | - Lin-Yue Lanry Yung
- Department of Chemical & Biomolecular Engineering, Faculty of Engineering, National University of Singapore, Singapore, 117585
| | - S Thameem Dheen
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore
| | - Boon Huat Bay
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore
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Genome-wide Profiling of Urinary Extracellular Vesicle microRNAs Associated With Diabetic Nephropathy in Type 1 Diabetes. Kidney Int Rep 2017; 3:555-572. [PMID: 29854963 PMCID: PMC5976846 DOI: 10.1016/j.ekir.2017.11.019] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 11/15/2017] [Accepted: 11/27/2017] [Indexed: 01/01/2023] Open
Abstract
Introduction Diabetic nephropathy (DN) is a form of progressive kidney disease that often leads to end-stage renal disease (ESRD). It is initiated by microvascular complications due to diabetes. Although microalbuminuria (MA) is the earliest clinical indication of DN among patients with type 1 diabetes (T1D), it lacks the sensitivity and specificity to detect the early onset of DN. Recently, microRNAs (miRNAs) have emerged as critical regulators in diabetes as well as various forms of kidney disease, including renal fibrosis, acute kidney injury, and progressive kidney disease. Additionally, circulating extracellular miRNAs, especially miRNAs packaged in extracellular vesicles (EVs), have garnered significant attention as potential noninvasive biomarkers for various diseases and health conditions. Methods As part of the University of Pittsburgh Epidemiology of Diabetes Complications (EDC) study, urine was collected from individuals with T1D with various grades of DN or MA (normal, overt, intermittent, and persistent) over a decade at prespecified intervals. We isolated EVs from urine and analyzed the small-RNA using NextGen sequencing. Results We identified a set of miRNAs that are enriched in urinary EVs compared with EV-depleted samples, and identified a number of miRNAs showing concentration changes associated with DN occurrence, MA status, and other variables, such as hemoglobin A1c levels. Conclusion Many of the miRNAs associated with DN occurrence or MA status directly target pathways associated with renal fibrosis (including transforming growth factor-β and phosphatase and tensin homolog), which is one of the major contributors to the pathology of DN. These miRNAs are potential biomarkers for DN and MA.
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25
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Chatterjee S, Verma SP, Pandey P. Profiling conserved biological pathways in Autosomal Dominant Polycystic Kidney Disorder (ADPKD) to elucidate key transcriptomic alterations regulating cystogenesis: A cross-species meta-analysis approach. Gene 2017; 627:434-450. [DOI: 10.1016/j.gene.2017.06.059] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 06/28/2017] [Accepted: 06/30/2017] [Indexed: 12/16/2022]
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Zhong X, Tu YJ, Li Y, Zhang P, Wang W, Chen SS, Li L, Chung ACK, Lan HY, Chen HY, Li GS, Wang L. Serum levels of WNT1-inducible signaling pathway protein-1 (WISP-1): a noninvasive biomarker of renal fibrosis in subjects with chronic kidney disease. Am J Transl Res 2017; 9:2920-2932. [PMID: 28670380 PMCID: PMC5489892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Accepted: 05/18/2017] [Indexed: 06/07/2023]
Abstract
WNT1-inducible signaling pathway protein-1 (WISP-1) is an extracellular matrix-related protein that plays multiple roles in cellular physiology and pathology. Accumulating evidence shows that WISP-1 is involved in the process underlying fibrotic diseases. However, the correlation between WISP-1 and renal fibrosis is unknown. In this study, we hypothesized that WISP-1 levels might be correlated with renal fibrosis and could be used as a noninvasive biomarker to screen for renal fibrosis in patients with chronic kidney disease (CKD). We first measured the WISP-1 expression levels using a transforming growth factor-β (TGF-β)-induced renal fibrosis tubular epithelial cell (TEC) model and a mouse model of obstructive nephropathy. We then evaluated the correlation between serum WISP-1 levels and fibrosis scores in biopsy-proven renal fibrosis of patients with CKD. Based on the findings from both in vivo and in vitro studies, the levels of WISP-1 and fibrotic parameters (collagen I, fibronectin and α-smooth muscle actin) were significantly increased in the fibrotic models. Consistently, patients with focal proliferative IgA nephropathy, focal segmental glomerular sclerosis and diabetic nephropathy displayed markedly elevated serum WISP-1 levels and fibrosis scores of renal biopsies compared with normal subjects and patients with minimal change disease (P<0.05). Importantly, the serum WISP-1 levels were positively correlated with fibrosis scores in the renal biopsies of these patients (r=0.475, P=0.0001). Thus, serum WISP-1 levels may be used as a potential noninvasive biomarker of renal fibrosis in patients with CKD.
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Affiliation(s)
- Xiang Zhong
- Department of Nephrology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of ChinaChengdu, China
| | - Yue Ju Tu
- Department of Nephrology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of ChinaChengdu, China
| | - Yi Li
- Department of Nephrology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of ChinaChengdu, China
| | - Ping Zhang
- Department of Nephrology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of ChinaChengdu, China
| | - Wei Wang
- Department of Nephrology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of ChinaChengdu, China
| | - Sha Sha Chen
- Department of Nephrology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of ChinaChengdu, China
| | - Li Li
- Laboratory of Pathology, West China Hospital, Sichuan UniversityChengdu, China
| | - Arthur CK Chung
- Partner State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, The Hong Kong Baptist UniversityHong Kong, China
- HKBU Institute for Research and Continuing EducationShenzhen, China
| | - Hui Yao Lan
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong KongHong Kong, China
| | - Hai Yong Chen
- School of Chinese Medicine, The University of Hong KongPokfulam, Hong Kong
- Department of Chinese Medicine, The University of Hong Kong-Shenzhen HospitalShenzhen, China
| | - Gui Sen Li
- Department of Nephrology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of ChinaChengdu, China
| | - Li Wang
- Department of Nephrology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of ChinaChengdu, China
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27
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Kocyigit I, Taheri S, Sener EF, Eroglu E, Ozturk F, Unal A, Korkmaz K, Zararsiz G, Sipahioglu MH, Ozkul Y, Tokgoz B, Oymak O, Ecder T, Axelsson J. Serum micro-rna profiles in patients with autosomal dominant polycystic kidney disease according to hypertension and renal function. BMC Nephrol 2017; 18:179. [PMID: 28558802 PMCID: PMC5450105 DOI: 10.1186/s12882-017-0600-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 05/23/2017] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary disorder with unclear disease mechanism. Currently, overt hypertension and increased renal volume are the best predictors of renal function. In this study, we assessed the usefulness of selected circulating microRNAs (miRs) to predict disease progress in a cohort with ADPKD. METHODS Eighty ADPKD patients (44.6 ± 12.7 years, 40% female, 65% hypertensive) and 50 healthy subjects (HS; 45.4 ± 12.7, 44% female) were enrolled in the study. Serum levels of 384 miRs were determined by Biomark Real Time PCR. Groups were compared using the limma method with multiple-testing correction as proposed by Smyth (corrected p < 0.01 considered significant). RESULTS Comparing ADPKD to HS, we found significant differences in blood levels of 18 miRs (3 more and 15 less abundant). Of these, miR-3907, miR-92a-3p, miR-25-3p and miR-21-5p all rose while miR-1587 and miR-3911 decreased as renal function declined in both cross-sectional and longitudinal analysis. Using ROC analysis, an increased baseline miR-3907 in the circulation predicted a > 10% loss of GFR over the following 12 months (cut-off >2.2 AU, sensitivity 83%, specificity 78%, area 0.872 [95% CI: 0.790-0.953, p < 0.001]). Adjusting for age and starting CKD stage using multiple binary logistic regression analysis did not abrogate the predictive value. CONCLUSION Increased copy numbers of miR-3907 in the circulation may predict ADPKD progression and suggest pathophysiological pathways worthy of further study.
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Affiliation(s)
- Ismail Kocyigit
- Department of Internal Medicine, Division of Nephrology, Erciyes University Medical Faculty, Kayseri, Turkey
| | - Serpil Taheri
- Department of Medical Biology, Erciyes University Medical Faculty, Kayseri, Turkey
| | - Elif Funda Sener
- Department of Medical Biology, Erciyes University Medical Faculty, Kayseri, Turkey
| | - Eray Eroglu
- Department of Internal Medicine, Division of Nephrology, Erciyes University Medical Faculty, Kayseri, Turkey
| | - Fahir Ozturk
- Department of Internal Medicine, Erciyes University Medical Faculty, Kayseri, Turkey
| | - Aydin Unal
- Department of Internal Medicine, Division of Nephrology, Erciyes University Medical Faculty, Kayseri, Turkey
| | - Kezban Korkmaz
- Betul-Ziya Eren Genome and Stem Cell Center, Erciyes University Medical Faculty, Kayseri, Turkey
| | - Gokmen Zararsiz
- Department of Biostatistics, Erciyes University, Kayseri, Turkey
| | - Murat Hayri Sipahioglu
- Department of Internal Medicine, Division of Nephrology, Erciyes University Medical Faculty, Kayseri, Turkey
| | - Yusuf Ozkul
- Betul-Ziya Eren Genome and Stem Cell Center, Erciyes University Medical Faculty, Kayseri, Turkey
| | - Bulent Tokgoz
- Department of Internal Medicine, Division of Nephrology, Erciyes University Medical Faculty, Kayseri, Turkey
| | - Oktay Oymak
- Department of Internal Medicine, Division of Nephrology, Erciyes University Medical Faculty, Kayseri, Turkey
| | - Tevfik Ecder
- Department of Internal Medicine, Division of Nephrology, Istanbul Bilim University, Istanbul, Turkey
| | - Jonas Axelsson
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska institutet, Karolinska University Hospital, Stockholm, Sweden. .,Department of Clinical Immunology, Karolinska University Hospital, C2:66 ImmTrans, 141 86, Stockholm, Sweden.
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Wang S, Wang J, Zhang Z, Miao H. Decreased miR-128 and increased miR-21 synergistically cause podocyte injury in sepsis. J Nephrol 2017; 30:543-550. [PMID: 28497421 DOI: 10.1007/s40620-017-0405-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 04/27/2017] [Indexed: 12/29/2022]
Abstract
OBJECTIVE Glomerular podocytes are injured in sepsis. We studied, in a sepsis patient, whether microRNAs (miRNAs) play a role in the podocyte injury. METHODS Podocytes were cultured and treated with lipopolysaccharide (LPS). Filtration barrier function of podocyte was analyzed with albumin influx assay. Nephrin level was analyzed with reverse transcription polymerase chain reaction (RT-PCR) and western blot. MiRNAs were detected using miRNAs PCR Array and in situ hybridization. MiRNA target sites were evaluated with luciferase reporter assays. RESULTS LPS impaired the filtration barrier function of podocytes. MiR-128 level was decreased and miR-21 level was increased in podocytes in vitro and in the sepsis patient. The decrease in miR-128 was sufficient to induce the loss of nephrin and the impairment of filtration barrier function, while the increase of miR-21 exacerbated the process. Snail and phosphatase and tensin homolog (PTEN) were identified as the targets of miR-128 and miR-21. Decreased miR-128 induced Snail expression, and the increased miR-21 stabilized Snail by regulating the PTEN/Akt/GSK3β pathway. Supplementation of miR-128 and inhibition of miR-21 suppressed Snail expression and prevented the podocyte injury induced by LPS. CONCLUSION Our study suggests that decreased miR-128 and increased miR-21 synergistically cause podocyte injury and are the potential therapeutic targets in sepsis.
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Affiliation(s)
- Shanshan Wang
- Department of Emergency, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
| | - Jun Wang
- Department of Emergency, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
| | - Zengdi Zhang
- Department of Emergency, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
| | - Hongjun Miao
- Department of Emergency, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China.
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29
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Paul P, Chakraborty A, Sarkar D, Langthasa M, Rahman M, Bari M, Singha RS, Malakar AK, Chakraborty S. Interplay between miRNAs and human diseases. J Cell Physiol 2017; 233:2007-2018. [PMID: 28181241 DOI: 10.1002/jcp.25854] [Citation(s) in RCA: 280] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 02/07/2017] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) are endogenous, non-coding RNAs, which have evoked a great deal of interest due to their importance in many aspects of homeostasis and diseases. MicroRNAs are stable and are essential components of gene regulatory networks. They play a crucial role in healthy individuals and their dysregulations have also been implicated in a wide range of diseases, including diabetes, cardiovascular disease, kidney disease, and cancer. This review summarized the current understanding of interactions between miRNAs and different diseases and their role in disease diagnosis and therapy.
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Affiliation(s)
- Prosenjit Paul
- Department of Biotechnology, Assam University, Silchar, Assam, India
| | | | - Debasree Sarkar
- Department of Biotechnology, Assam University, Silchar, Assam, India
| | | | - Musfhia Rahman
- Department of Biotechnology, Assam University, Silchar, Assam, India
| | - Minakshi Bari
- Department of Biotechnology, Assam University, Silchar, Assam, India
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30
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Khurana R, Ranches G, Schafferer S, Lukasser M, Rudnicki M, Mayer G, Hüttenhofer A. Identification of urinary exosomal noncoding RNAs as novel biomarkers in chronic kidney disease. RNA (NEW YORK, N.Y.) 2017; 23:142-152. [PMID: 27872161 PMCID: PMC5238789 DOI: 10.1261/rna.058834.116] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 11/08/2016] [Indexed: 06/06/2023]
Abstract
In chronic kidney disease (CKD), the decline in the glomerular filtration rate is associated with increased morbidity and mortality and thus poses a major challenge for healthcare systems. While the contribution of tissue-derived miRNAs and mRNAs to CKD progression has been extensively studied, little is known about the role of urinary exosomes and their association with CKD. Exosomes are small, membrane-derived endocytic vesicles that contribute to cell-to-cell communication and are present in various body fluids, such as blood or urine. Next-generation sequencing approaches have revealed that exosomes are enriched in noncoding RNAs and thus exhibit great potential for sensitive nucleic acid biomarkers in various human diseases. Therefore, in this study we aimed to identify urinary exosomal ncRNAs as novel biomarkers for diagnosis of CKD. Since up to now most approaches have focused on the class of miRNAs, we extended our analysis to several other noncoding RNA classes, such as tRNAs, tRNA fragments (tRFs), mitochondrial tRNAs, or lincRNAs. For their computational identification from RNA-seq data, we developed a novel computational pipeline, designated as ncRNASeqScan. By these analyses, in CKD patients we identified 30 differentially expressed ncRNAs, derived from urinary exosomes, as suitable biomarkers for early diagnosis. Thereby, miRNA-181a appeared as the most robust and stable potential biomarker, being significantly decreased by about 200-fold in exosomes of CKD patients compared to healthy controls. Using a cell culture system for CKD indicated that urinary exosomes might indeed originate from renal proximal tubular epithelial cells.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Biomarkers/urine
- Case-Control Studies
- Early Diagnosis
- Epithelial Cells/metabolism
- Epithelial Cells/pathology
- Exosomes/chemistry
- Exosomes/metabolism
- Female
- Glomerular Filtration Rate
- High-Throughput Nucleotide Sequencing
- Humans
- Kidney Tubules, Proximal/metabolism
- Kidney Tubules, Proximal/pathology
- Male
- MicroRNAs/urine
- Middle Aged
- Molecular Sequence Annotation
- RNA/urine
- RNA, Long Noncoding/urine
- RNA, Mitochondrial
- RNA, Transfer/urine
- Renal Insufficiency, Chronic/diagnosis
- Renal Insufficiency, Chronic/pathology
- Renal Insufficiency, Chronic/urine
- Sequence Analysis, RNA
- Severity of Illness Index
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Affiliation(s)
- Rimpi Khurana
- Division of Genomics and RNomics, Biocenter, Medical University Innsbruck, 6020 Innsbruck, Austria
| | - Glory Ranches
- Division of Genomics and RNomics, Biocenter, Medical University Innsbruck, 6020 Innsbruck, Austria
| | - Simon Schafferer
- Division of Genomics and RNomics, Biocenter, Medical University Innsbruck, 6020 Innsbruck, Austria
| | - Melanie Lukasser
- Division of Genomics and RNomics, Biocenter, Medical University Innsbruck, 6020 Innsbruck, Austria
| | - Michael Rudnicki
- Department of Internal Medicine IV, Nephrology and Hypertension, Medical University Innsbruck, 6020 Innsbruck, Austria
| | - Gert Mayer
- Department of Internal Medicine IV, Nephrology and Hypertension, Medical University Innsbruck, 6020 Innsbruck, Austria
| | - Alexander Hüttenhofer
- Division of Genomics and RNomics, Biocenter, Medical University Innsbruck, 6020 Innsbruck, Austria
- i-med GenomeSeq Core, 6020 Innsbruck, Austria
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Yao K, Ricardo SD. Mesenchymal stem cells as novel micro-ribonucleic acid delivery vehicles in kidney disease. Nephrology (Carlton) 2017; 21:363-71. [PMID: 26437381 DOI: 10.1111/nep.12643] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2015] [Revised: 08/19/2015] [Accepted: 09/30/2015] [Indexed: 12/11/2022]
Abstract
MicroRNAs (miRNAs) are short single strands of RNA responsible for post-transcriptional regulation of gene expression and have been implicated in the pathogenesis of chronic kidney disease (CKD). Emerging evidence reports that miRNAs can reduce kidney fibrosis through regulation of targets associated with collagen and extracellular matrix accumulation. However, the development of miRNA therapies has been hampered by the lack of targeted and sustainable methods of systemic miRNA delivery. Mesenchymal stem cells (MSCs) provide a promising miRNA delivery platform to overcome toxicity, the potential for insertional mutations and the low efficiency of previous methods. MSCs are endogenously immunoprivileged and home to sites of inflammation. They also release trophic growth factors to modulate the immune system, alter the polarization of macrophages and provide renal protection and repair. The potential to engineer MSCs to express or overexpress miRNAs, released by exosomes, may enhance their natural functions. Clinical studies are already being conducted individually for the use of miRNAs in cancer and MSCs in diseases associated with CKD. Hence, the combination of miRNAs and MSCs may provide an unparalleled cell-based therapy for treating CKD.
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Affiliation(s)
- Kevin Yao
- Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia
| | - Sharon D Ricardo
- Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia
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Liu X, Edinger RS, Klemens CA, Phua YL, Bodnar AJ, LaFramboise WA, Ho J, Butterworth MB. A MicroRNA Cluster miR-23-24-27 Is Upregulated by Aldosterone in the Distal Kidney Nephron Where it Alters Sodium Transport. J Cell Physiol 2017; 232:1306-1317. [PMID: 27636893 DOI: 10.1002/jcp.25599] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 09/14/2016] [Indexed: 01/09/2023]
Abstract
The epithelial sodium channel (ENaC) is expressed in the epithelial cells of the distal convoluted tubules, connecting tubules, and cortical collecting duct (CCD) in the kidney nephron. Under the regulation of the steroid hormone aldosterone, ENaC is a major determinant of sodium (Na+ ) and water balance. The ability of aldosterone to regulate microRNAs (miRs) in the kidney has recently been realized, but the role of miRs in Na+ regulation has not been well established. Here we demonstrate that expression of a miR cluster mmu-miR-23-24-27, is upregulated in the CCD by aldosterone stimulation both in vitro and in vivo. Increasing the expression of these miRs increased Na+ transport in the absence of aldosterone stimulation. Potential miR targets were evaluated and miR-27a/b was verified to bind to the 3'-untranslated region of intersectin-2, a multi-domain protein expressed in the distal kidney nephron and involved in the regulation of membrane trafficking. Expression of Itsn2 mRNA and protein was decreased after aldosterone stimulation. Depletion of Itsn2 expression, mimicking aldosterone regulation, increased ENaC-mediated Na+ transport, while Itsn2 overexpression reduced ENaC's function. These findings reinforce a role for miRs in aldosterone regulation of Na+ transport, and implicate miR-27 in aldosterone's action via a novel target. J. Cell. Physiol. 232: 1306-1317, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Xiaoning Liu
- Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Robert S Edinger
- Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Christine A Klemens
- Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Yu L Phua
- Division of Nephrology in the Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Andrew J Bodnar
- Division of Nephrology in the Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - William A LaFramboise
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Jacqueline Ho
- Division of Nephrology in the Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Michael B Butterworth
- Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Jaswani P, Prakash S, Dhar A, Sharma RK, Prasad N, Agrawal S. MicroRNAs Involvement in Renal Pathophysiology: A Bird's Eye View. Indian J Nephrol 2017; 27:337-341. [PMID: 28904427 PMCID: PMC5590408 DOI: 10.4103/ijn.ijn_264_16] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
MicroRNAs (miRNAs) are known to suppress gene expression by binding to messenger RNAs and in turn regulate different pathophysiological processes. Transforming growth factor-β, mitogen-activated protein kinase signaling, and Wnt signaling-like major pathways associated with miRNAs are involved with kidney diseases. The discovery of miRNAs has provided new insights into kidney pathologies and may provide effective therapeutic strategies. Research has demonstrated the role of miRNAs in a variety of kidney diseases including diabetic nephropathy, lupus nephritis, hypertension, nephritic syndrome, acute kidney injury, renal cell carcinoma, and renal fibrosis. miRNAs are implicated as playing a role in these diseases due to their role in apoptosis, cell proliferation, differentiation, and development. As miRNAs have been detected in a stable condition in different biological fluids, they have the potential to be tools to study the pathogenesis of human diseases with a great potential to be used in disease diagnosis and prognosis. The purpose of this review is to examine the role of miRNA in kidney disease.
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Affiliation(s)
- P Jaswani
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - S Prakash
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - A Dhar
- Department of Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - R K Sharma
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - N Prasad
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - S Agrawal
- Department of Hematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
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Chen SJ, Wu P, Sun LJ, Zhou B, Niu W, Liu S, Lin FJ, Jiang GR. miR-204 regulates epithelial-mesenchymal transition by targeting SP1 in the tubular epithelial cells after acute kidney injury induced by ischemia-reperfusion. Oncol Rep 2016; 37:1148-1158. [PMID: 27959449 DOI: 10.3892/or.2016.5294] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Accepted: 11/29/2016] [Indexed: 11/05/2022] Open
Abstract
Acute kidney injury (AKI) is a disease where kidney function is lost almost instantaneously; it can develop very rapidly over few hours to maximum of few days. Despite the advent of technology, the clinical management against this disease is very poor, and most of the time it is life-threatening. AKI has been actively regulated by extracellular matrix proteins (ECM), however, its underlying mechanism of regulation during AKI progression is very poorly understood. In this study, we explored the integrated network of mRNA and microRNAs (miRNAs) that maintains the progression of ECM after induction of AKI by lethal ischemia. To identify key regulators of ECM, we screened large number of transcriptomes using laser capture microdissection (LCM) technique in addition to microarray and RT-qPCR. Our result clearly showed that 9 miRNAs including miR-21, miR-483, miR-5115, miR-204e, miR-128, miR-181c, miR-203, miR-204 and miR-204c were highly regulated, out of which miR-204 expression change (decrease) was most drastic during ischemia/reperfusion. Detail mechanistic study utilizing combined experimental and computational approach revealed that TGF-β signaling pathway was potentially modulated by deregulated miRNA-204 through SP1, where the TGF-β signaling pathway plays a vital role in ECM regulation. Apart from targeting SP1 and antagonizing epithelial-mesenchymal transition (EMT) signaling our result also showed that miR-204 protects interstitial tissue of renal tubules from chronic fibrotic change. Altogether our study provides sufficient details of how miRNA mediated ECM regulation occur during AKI, which can be effectively utilized in future for better AKI management and diagnosis.
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Affiliation(s)
- Shun-Jie Chen
- Department of Nephrology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Ping Wu
- Department of Nephrology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Li-Jing Sun
- Department of Nephrology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Bo Zhou
- Department of Nephrology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Wei Niu
- Department of Nephrology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Shuang Liu
- Department of Nephrology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Fu-Jun Lin
- Department of Nephrology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Geng-Ru Jiang
- Department of Nephrology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
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35
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Fan PC, Chen CC, Chen YC, Chang YS, Chu PH. MicroRNAs in acute kidney injury. Hum Genomics 2016; 10:29. [PMID: 27608623 PMCID: PMC5016954 DOI: 10.1186/s40246-016-0085-z] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2016] [Accepted: 08/31/2016] [Indexed: 12/19/2022] Open
Abstract
Acute kidney injury (AKI) is an important clinical issue that is associated with significant morbidity and mortality. Despite research advances over the past decades, the complex pathophysiology of AKI is not fully understood. The regulatory mechanisms underlying post-AKI repair and fibrosis have not been clarified either. Furthermore, there is no definitively effective treatment for AKI. MicroRNAs (miRNAs) are endogenous single-stranded noncoding RNAs of 19~23 nucleotides that have been shown to be crucial to the post-transcriptional regulation of various cellular biological functions, including proliferation, differentiation, metabolism, and apoptosis. In addition to being fundamental to normal development and physiology, miRNAs also play important roles in various human diseases. In AKI, some miRNAs appear to act pathogenically by promoting inflammation, apoptosis, and fibrosis, while others may act protectively by exerting anti-inflammatory, anti-apoptotic, anti-fibrotic, and pro-angiogenic effects. Thus, miRNAs have not only emerged as novel biomarkers for AKI; they also hold promise to be potential therapeutic targets.
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Affiliation(s)
- Pei-Chun Fan
- Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Chia-Chun Chen
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Yung-Chang Chen
- Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
| | - Yu-Sun Chang
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Pao-Hsien Chu
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taipei, Taiwan. .,Healthcare Center, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taipei, Taiwan. .,Heart Failure Center, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taipei, Taiwan. .,Department of Cardiology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, 199 Tung Hwa North Road, Taipei, 105, Taiwan.
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36
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Lakhia R, Hajarnis S, Williams D, Aboudehen K, Yheskel M, Xing C, Hatley ME, Torres VE, Wallace DP, Patel V. MicroRNA-21 Aggravates Cyst Growth in a Model of Polycystic Kidney Disease. J Am Soc Nephrol 2016; 27:2319-30. [PMID: 26677864 PMCID: PMC4978047 DOI: 10.1681/asn.2015060634] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 10/27/2015] [Indexed: 12/31/2022] Open
Abstract
Autosomal dominant polycystic kidney disease (ADPKD), one of the most common monogenetic disorders, is characterized by kidney failure caused by bilateral renal cyst growth. MicroRNAs (miRs) have been implicated in numerous diseases, but the role of these noncoding RNAs in ADPKD pathogenesis is still poorly defined. Here, we investigated the role of miR-21, an oncogenic miR, in kidney cyst growth. We found that transcriptional activation of miR-21 is a common feature of murine PKD. Furthermore, compared with renal tubules from kidney samples of normal controls, cysts in kidney samples from patients with ADPKD had increased levels of miR-21. cAMP signaling, a key pathogenic pathway in PKD, transactivated miR-21 promoter in kidney cells and promoted miR-21 expression in cystic kidneys of mice. Genetic deletion of miR-21 attenuated cyst burden, reduced kidney injury, and improved survival of an orthologous model of ADPKD. RNA sequencing analysis and additional in vivo assays showed that miR-21 inhibits apoptosis of cyst epithelial cells, likely through direct repression of its target gene programmed cell death 4 Thus, miR-21 functions downstream of the cAMP pathway and promotes disease progression in experimental PKD. Our results suggest that inhibiting miR-21 is a potential new therapeutic approach to slow cyst growth in PKD.
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Affiliation(s)
| | | | | | - Karam Aboudehen
- Department of Internal Medicine, University of Minnesota Medical School, Minneapolis, Minnesota
| | | | - Chao Xing
- McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Mark E Hatley
- Department of Oncology, St. Jude's Children's Research Hospital, Memphis, Tennessee
| | - Vicente E Torres
- Departments of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota; and
| | - Darren P Wallace
- Department of Internal Medicine and the Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas
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37
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Saigusa T, Bell PD. Molecular pathways and therapies in autosomal-dominant polycystic kidney disease. Physiology (Bethesda) 2016; 30:195-207. [PMID: 25933820 DOI: 10.1152/physiol.00032.2014] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Autosomal-dominant polycystic kidney disease (ADPKD) is the most prevalent inherited renal disease, characterized by multiple cysts that can eventually lead to kidney failure. Studies investigating the role of primary cilia and polycystins have significantly advanced our understanding of the pathogenesis of PKD. This review will present clinical and basic aspects of ADPKD, review current concepts of PKD pathogenesis, evaluate potential therapeutic targets, and highlight challenges for future clinical studies.
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Affiliation(s)
- Takamitsu Saigusa
- Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, South Carolina; and Ralph Johnson VA Medical Center, Charleston, South Carolina
| | - P Darwin Bell
- Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, South Carolina; and Ralph Johnson VA Medical Center, Charleston, South Carolina
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38
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Abstract
Epigenetic regulation refers to heritable changes in gene expression that do not involve any alteration of the DNA sequence. DNA methylation, histone modification, and gene regulation by microRNAs are well-known epigenetic modulations that are closely associated with several cellular processes and diverse disease states, such as cancers, even under precancerous conditions. More recently, several studies have indicated that epigenetic changes may be associated with renal cystic diseases, including autosomal dominant polycystic kidney disease, and the restoration of altered epigenetic factors may become a therapeutic target of renal cystic disease and would be expected to have minimal side effects. This review focuses on recently reported findings on epigenetic and considers the potential of targeting epigenetic regulation as a novel therapeutic approach to control cystogenesis.
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39
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Mukhadi S, Hull R, Mbita Z, Dlamini Z. The Role of MicroRNAs in Kidney Disease. Noncoding RNA 2015; 1:192-221. [PMID: 29861424 PMCID: PMC5932548 DOI: 10.3390/ncrna1030192] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 09/28/2015] [Accepted: 11/08/2015] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs) are short noncoding RNAs that regulate pathophysiological processes that suppress gene expression by binding to messenger RNAs. These biomolecules can be used to study gene regulation and protein expression, which will allow better understanding of many biological processes such as cell cycle progression and apoptosis that control the fate of cells. Several pathways have also been implicated to be involved in kidney diseases such as Transforming Growth Factor-β, Mitogen-Activated Protein Kinase signaling, and Wnt signaling pathways. The discovery of miRNAs has provided new insights into kidney pathologies and may provide new innovative and effective therapeutic strategies. Research has demonstrated the role of miRNAs in a variety of kidney diseases including renal cell carcinoma, diabetic nephropathy, nephritic syndrome, renal fibrosis, lupus nephritis and acute pyelonephritis. MiRNAs are implicated as playing a role in these diseases due to their role in apoptosis, cell proliferation, differentiation and development. As miRNAs have been detected in a stable condition in different biological fluids, they have the potential to be tools to study the pathogenesis of human diseases with a great potential to be used in disease prognosis and diagnosis. The purpose of this review is to examine the role of miRNA in kidney disease.
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Affiliation(s)
- Sydwell Mukhadi
- Forensic Science Laboratory, 730 Pretorius street, Arcadia 0083, South Africa.
| | - Rodney Hull
- College of Agriculture and Environmental Sciences, University of South Africa, Private Bag X6, Florida 1709, Johannesburg 1709, South Africa.
| | - Zukile Mbita
- Department of Biochemistry, Microbiology and Biotechnology, University of Limpopo, Private Bag x1106, Sovenga 0727, South Africa.
| | - Zodwa Dlamini
- Research, Innovation & Engagements Portfolio, Mangosuthu University of Technology, Durban 4031, South Africa.
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40
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MicroRNAs in the Cholangiopathies: Pathogenesis, Diagnosis, and Treatment. J Clin Med 2015; 4:1688-712. [PMID: 26343736 PMCID: PMC4600153 DOI: 10.3390/jcm4091688] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 08/07/2015] [Accepted: 08/11/2015] [Indexed: 12/23/2022] Open
Abstract
The cholangiopathies are a group of liver diseases resulting from different etiologies but with the cholangiocyte as the primary target. As a group, the cholangiopathies result in significant morbidity and mortality and represent one of the main indications for liver transplant in both children and adults. Contributing to this situation is the absence of a thorough understanding of their pathogenesis and a lack of adequate diagnostic and prognostic biomarkers. MicroRNAs are small non-coding RNAs that modify gene expression post-transcriptionally. They have been implicated in the pathogenesis of many diseases, including the cholangiopathies. Thus, in this review we provide an overview of the literature on miRNAs in the cholangiopathies and discuss future research directions.
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41
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Hajarnis SS, Patel V, Aboudehen K, Attanasio M, Cobo-Stark P, Pontoglio M, Igarashi P. Transcription Factor Hepatocyte Nuclear Factor-1β (HNF-1β) Regulates MicroRNA-200 Expression through a Long Noncoding RNA. J Biol Chem 2015; 290:24793-805. [PMID: 26292219 DOI: 10.1074/jbc.m115.670646] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2015] [Indexed: 12/31/2022] Open
Abstract
The transcription factor hepatocyte nuclear factor-1β (HNF-1β) regulates tissue-specific gene expression in the kidney and other epithelial organs. Mutations of HNF-1β produce kidney cysts, and previous studies have shown that HNF-1β regulates the transcription of cystic disease genes, including Pkd2 and Pkhd1. Here, we combined chromatin immunoprecipitation and next-generation sequencing (ChIP-Seq) with microarray analysis to identify microRNAs (miRNAs) that are directly regulated by HNF-1β in renal epithelial cells. These studies identified members of the epithelial-specific miR-200 family (miR-200b/200a/429) as novel transcriptional targets of HNF-1β. HNF-1β binds to two evolutionarily conserved sites located 28 kb upstream to miR-200b. Luciferase reporter assays showed that the HNF-1β binding sites were located within a promoter that was active in renal epithelial cells. Mutations of the HNF-1β binding sites abolished promoter activity. RT-PCR analysis revealed that a long noncoding RNA (lncRNA) is transcribed from the promoter and encodes the miR-200 cluster. Inhibition of the lncRNA with siRNAs decreased the levels of miR-200 but did not affect expression of the Ttll10 host gene. The expression of the lncRNA and miR-200 was decreased in kidneys from HNF-1β knock-out mice and renal epithelial cells expressing dominant-negative mutant HNF-1β. The expression of miR-200 targets, Zeb2 and Pkd1, was increased in HNF-1β knock-out kidneys and in cells expressing mutant HNF-1β. Overexpression of miR-200 decreased the expression of Zeb2 and Pkd1 in HNF-1β mutant cells. These studies reveal a novel pathway whereby HNF-1β directly contributes to the control of miRNAs that are involved in epithelial-mesenchymal transition and cystic kidney disease.
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Affiliation(s)
| | | | | | | | | | - Marco Pontoglio
- Départment de Génétique et Développement, INSERM U1016, CNRS UMR 8104, Université Paris-Descartes. Institut Cochin, 75014 Paris, France
| | - Peter Igarashi
- From the Departments of Internal Medicine and Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390 and
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42
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Abstract
PURPOSE OF REVIEW Cystic kidney diseases are common renal disorders characterized by the formation of fluid-filled epithelial cysts in the kidneys. The progressive growth and expansion of the renal cysts replace existing renal tissue within the renal parenchyma, leading to reduced renal function. While several genes have been identified in association with inherited causes of cystic kidney disease, the molecular mechanisms that regulate these genes in the context of post-transcriptional regulation are still poorly understood. There is increasing evidence that microRNA (miRNA) dysregulation is associated with the pathogenesis of cystic kidney disease. RECENT FINDINGS In this review, recent studies that implicate dysregulation of miRNA expression in cystogenesis will be discussed. The relationship of specific miRNAs, such as the miR-17∼92 cluster and cystic kidney disease, miR-92a and von Hippel-Lindau syndrome, and alterations in LIN28-LET7 expression in Wilms tumor will be explored. SUMMARY At present, there are no specific treatments available for patients with cystic kidney disease. Understanding and identifying specific miRNAs involved in the pathogenesis of these disorders may have the potential to lead to the development of novel therapies and biomarkers.
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Butterworth MB. MicroRNAs and the regulation of aldosterone signaling in the kidney. Am J Physiol Cell Physiol 2015; 308:C521-7. [PMID: 25673770 DOI: 10.1152/ajpcell.00026.2015] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 02/11/2015] [Indexed: 01/22/2023]
Abstract
The role of small noncoding RNAs, termed microRNAs (miRs), in development and disease has been recognized for many years. The number of miRs and regulated targets that reinforce a role for miRs in human disease and disease progression is ever-increasing. However, less is known about the involvement of miRs in steady-state, nondisease homeostatic pathways. In the kidney, much of the regulated ion transport is under the control of hormonal signaling. Evidence is emerging that miRs are involved in the hormonal regulation of kidney function and, particularly, in ion transport. In this short review, the production and intra- and extracellular signaling of miRs and the involvement of miRs in kidney disease are discussed. The discussion also focuses on the role of these small biological molecules in the homeostatic control of ion transport in the kidney. MiR regulation of and by corticosteroid hormones, in particular the mineralocorticoid hormone aldosterone, is considered. While information about the role of aldosterone-regulated miRs in the kidney is limited, an increase in the research in this area will undoubtedly highlight the involvement of miRs as central mediators of hormonal signaling in normal physiology.
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Affiliation(s)
- Michael B Butterworth
- Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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44
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Lopez-Giacoman S, Madero M. Biomarkers in chronic kidney disease, from kidney function to kidney damage. World J Nephrol 2015; 4:57-73. [PMID: 25664247 PMCID: PMC4317628 DOI: 10.5527/wjn.v4.i1.57] [Citation(s) in RCA: 212] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 10/21/2014] [Accepted: 11/10/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic kidney disease (CKD) typically evolves over many years, with a long latent period when the disease is clinically silent and therefore diagnosis, evaluation and treatment is based mainly on biomarkers that assess kidney function. Glomerular filtration rate (GFR) remains the ideal marker of kidney function. Unfortunately measuring GFR is time consuming and therefore GFR is usually estimated from equations that take into account endogenous filtration markers like serum creatinine (SCr) and cystatin C (CysC). Other biomarkers such as albuminuria may precede kidney function decline and have demonstrated to have strong associations with disease progression and outcomes. New potential biomarkers have arisen with the promise of detecting kidney damage prior to the currently used markers. The aim of this review is to discuss the utility of the GFR estimating equations and biomarkers in CKD and the different clinical settings where these should be applied. The CKD-Epidemiology Collaboration equation performs better than the modification of diet in renal disease equation, especially at GFR above 60 mL/min per 1.73 m2. Equations combining CysC and SCr perform better than the equations using either CysC or SCr alone and are recommended in situations where CKD needs to be confirmed. Combining creatinine, CysC and urine albumin to creatinine ratio improves risk stratification for kidney disease progression and mortality. Kidney injury molecule and neutrophil gelatinase-associated lipocalin are considered reasonable biomarkers in urine and plasma to determine severity and prognosis of CKD.
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45
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Gradilone SA, O’Hara SP, Masyuk TV, Pisarello MJL, LaRusso NF. MicroRNAs and benign biliary tract diseases. Semin Liver Dis 2015; 35:26-35. [PMID: 25632932 PMCID: PMC4413449 DOI: 10.1055/s-0034-1397346] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Cholangiocytes, the epithelial cells lining the biliary tree, represent only a small portion of the total liver cell population (3-5%), but they are responsible for the secretion of up to 40% of total daily bile volume. In addition, cholangiocytes are the target of a diverse group of liver diseases affecting the biliary tract, the cholangiopathies; for most of these conditions, the pathological mechanisms are unclear. MicroRNAs (miRNAs) are small, noncoding RNAs that posttranscriptionally regulate gene expression. Thus, it is not surprising that altered miRNA profiles underlie the dysregulation of several proteins involved in the pathobiology of the cholangiopathies, as well as showing promise as diagnostic and prognostic tools. Here the authors review recent work relevant to the role of miRNAs in the etiopathogenesis of several of the cholangiopathies (i.e., fibroinflammatory cholangiopathies and polycystic liver diseases), discuss their value as prognostic and diagnostic tools, and provide suggestions for further research.
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Affiliation(s)
- Sergio A. Gradilone
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota,The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Steven P. O’Hara
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota
| | - Tetyana V. Masyuk
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota
| | - Maria Jose Lorenzo Pisarello
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota
| | - Nicholas F. LaRusso
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota
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46
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Papagregoriou G. MicroRNAs in Disease. GENOMIC ELEMENTS IN HEALTH, DISEASE AND EVOLUTION 2015:17-46. [DOI: 10.1007/978-1-4939-3070-8_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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47
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48
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O’Hara SP, Gradilone SA, Masyuk TV, Tabibian JH, LaRusso NF. MicroRNAs in Cholangiopathies. CURRENT PATHOBIOLOGY REPORTS 2014; 2:133-142. [PMID: 25097819 PMCID: PMC4119442 DOI: 10.1007/s40139-014-0048-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Cholangiocytes, the cells lining bile ducts, comprise a small fraction of the total cellular component of the liver, yet perform the essential role of bile modification and transport of biliary and blood constituents. Cholangiopathies are a diverse group of biliary disorders with the cholangiocyte as the target cell; the etiopathogenesis of most cholangiopathies remains obscure. MicroRNAs are small non-coding RNAs that post-transcriptionally regulate gene expression. These small RNAs may not only be involved in the etiopathogenesis of disease, but are showing promise as diagnostic and prognostic tools. In this brief review, we summarize recent work regarding the role of microRNAs in the etiopathogenesis of several cholangiopathies, and discuss their utility as prognostic and diagnostic tools.
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Affiliation(s)
- Steven P. O’Hara
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota 55905, USA
| | - Sergio A. Gradilone
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota 55905, USA
| | - Tetyana V. Masyuk
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota 55905, USA
| | - James H. Tabibian
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota 55905, USA
| | - Nicholas F. LaRusso
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota 55905, USA
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49
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Discovery of an integrative network of microRNAs and transcriptomics changes for acute kidney injury. Kidney Int 2014; 86:943-53. [PMID: 24759152 DOI: 10.1038/ki.2014.117] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2013] [Revised: 02/09/2014] [Accepted: 03/06/2014] [Indexed: 12/19/2022]
Abstract
The contribution of miRNA to the pathogenesis of acute kidney injury (AKI) is not well understood. Here we evaluated an integrative network of miRNAs and mRNA data to discover a possible master regulator of AKI. Microarray analyses of the kidneys of mice treated with cisplatin were used to extract putative miRNAs that cause renal injury. Of them, miR-122 was mostly downregulated by cisplatin, whereas miR-34a was upregulated. A network integrating dysregulated miRNAs and altered mRNA expression along with target prediction enabled us to identify Foxo3 as a core protein to activate p53. The miR-122 inhibited Foxo3 translation as assessed using an miR mimic, an inhibitor, and a Foxo3 3'-UTR reporter. In a mouse model, Foxo3 levels paralleled the degree of tubular injury. The role of decreased miR-122 in inducing Foxo3 during AKI was strengthened by the ability of the miR-122 mimic or inhibitor to replicate results. Increase in miR-34a also promoted the acetylation of Foxo3 by repressing Sirt1. Consistently, cisplatin facilitated the binding of Foxo3 and p53 for activation, which depended not only on decreased miR-122 but also on increased miR-34a. Other nephrotoxicants had similar effects. Among targets of p53, Phlda3 was robustly induced by cisplatin, causing tubular injury. Consistently, treatment with miR mimics and/or inhibitors, or with Foxo3 and Phlda3 siRNAs, modulated apoptosis. Thus, our results uncovered an miR integrative network regulating toxicant-induced AKI and identified Foxo3 as a bridge molecule to the p53 pathway.
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50
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Yu J. miRNAs in mammalian ureteric bud development. Pediatr Nephrol 2014; 29:745-9. [PMID: 24452329 DOI: 10.1007/s00467-013-2734-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2013] [Revised: 12/06/2013] [Accepted: 12/12/2013] [Indexed: 12/20/2022]
Abstract
The collecting duct network and the urothelium of the ureter of the metanephric kidney are derived from the ureteric bud epithelium, initially an outgrowth from the caudal end of the Wolffian duct at the onset of the metanephric kidney development. The tips of the ureteric bud epithelium undergo reiterative branching morphogenesis, which generates more tips and trunks, whereas the ureteric trunks grow and differentiate into principal cells and intercalated cells of the collecting ducts that regulate body water and acid-base homeostasis. microRNAs (miRNAs) are a family of small non-coding RNAs that regulate a diversity of biological processes including organogenesis, mostly by negatively regulating their target gene expression. In this review, I will summarize the current knowledge on the critical roles of miRNAs expressed in the ureteric bud epithelium in ureteric bud morphogenesis and differentiation, including ureteric bud branching morphogenesis, collecting duct terminal differentiation, cystogenesis of the collecting ducts, and ureter development.
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Affiliation(s)
- Jing Yu
- Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA,
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