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Functional characterization and therapeutic assessment of long non-coding RNAs in isolated CD73+/platelet-derived growth factor receptor ß +-cells in kidney fibrosis

English title Functional characterization and therapeutic assessment of long non-coding RNAs in isolated CD73+/platelet-derived growth factor receptor ß +-cells in kidney fibrosis
Applicant Lorenzen Johan
Number 179347
Funding scheme Project funding
Research institution Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Pathophysiology
Start/End 01.04.2018 - 31.03.2022
Approved amount 414'009.00
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All Disciplines (2)

Discipline
Pathophysiology
Internal Medicine

Keywords (3)

lange nicht-kodierende RNA; chronische Nierenerkrankung; Nierenfibrose

Lay Summary (German)

Lead
Die Nierenfibrose ist vergesellschaftet mit einer Reihe von verschiedenen Nierenerkrankungen. Seine Progression ist ein entscheidender Faktor für die Entwicklung der terminalen Niereninsuffizienz. Der zelluläre Ursprung von Matrix-produzierenden Zellen der Niere wurde in der Vergangenheit viel diskutiert. Kürzlich wurde in eleganten Fate-Tracing-Experimenten gezeigt, dass CD73+/platelet-derived growth factor receptor ß+ (PDGFR-ß) Perizyten die Hauptquelle für matrixproduzierende Zellen in der Niere sind. Die Mechanismen, die die Transdifferenzierung von Perizyten-zu-Myofibroblasten steuern, sind nicht vollständig aufgeklärt. Nicht-kodierende RNAs könnten wichtige Regulatoren dieses Prozesses sein. Lange nicht-kodierende RNAs (lncRNAs) sind neue wichtige epigenetische Regulatoren der zellulären Funktion.
Lay summary
Im vorliegenden Antrag isolierten und charakterisierten wir CD73 + / PDGFR-ß + -Zellen aus Mausnieren in einem Angiotensin-II-induzierten Nierenfibrose-Modell in Vorversuchen. Anschließend wurde isolierte RNA von CD73 + / PDGFR-ß + -Zellen einem globalen lncRNA-Expressionsprofil unterzogen. Die Antisense-lncRNA X zählte zu den am höchsten hochregulierten Kandidaten. Folgende spezifische Ziele werden im vorliegenden Antrag untersucht: 1. Analyse der lncRNA X Antisense-Transkript-Expression in Nierenbiopsien von Patienten mit verschiedenen Ätiologien der chronischen Nierenerkrankungen. 2. Entwicklung eines neuen lncRNA X  - basierten therapeutischen Ansatzes zur Verbesserung der Fibroseentwicklung in 2 etablierten Fibrosemodellen: Ang II - induzierte Fibrose und Nierenfibrose bei unilateraler Ureterobstruktion 3. Untersuchung der mechanistischen Rolle von lncRNA X in vitro sowie seiner transkriptionellen Regulatoren und Zielgene.
Direct link to Lay Summary Last update: 09.04.2018

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Publication
Circular RNA-based biomarkers in blood of patients with Fabry disease and related phenotypes
Nowak Albina, Haddad George, Kistler Andreas D, Nlandu-Khodo Stellor, Beuschlein Felix, Wüthrich Rudolf P, Lorenzen Johan M, Kölling Malte (2022), Circular RNA-based biomarkers in blood of patients with Fabry disease and related phenotypes, in Journal of Medical Genetics, 59(3), 279-286.
Circular RNAs in kidney disease and cancer
van Zonneveld Anton Jan, Kölling Malte, Bijkerk Roel, Lorenzen Johan M. (2021), Circular RNAs in kidney disease and cancer, in Nature Reviews Nephrology, 17(12), 814-826.
Safety of Kidney Biopsy when Performed as an Outpatient Procedure
Bonani Marco, Seeger Harald, Weber Nina, Lorenzen Johan M., Wüthrich Rudolf P., Kistler Andreas D. (2021), Safety of Kidney Biopsy when Performed as an Outpatient Procedure, in Kidney and Blood Pressure Research, 46(3), 310-322.
Altered glycosylation of IgG4 promotes lectin complement pathway activation in anti-PLA2R1–associated membranous nephropathy
Haddad George, Lorenzen Johan M., Ma Hong, de Haan Noortje, Seeger Harald, Zaghrini Christelle, Brandt Simone, Kölling Malte, Wegmann Urs, Kiss Bence, Pál Gábor, Gál Péter, Wüthrich Rudolf P., Wuhrer Manfred, Beck Laurence H., Salant David J., Lambeau Gérard, Kistler Andreas D. (2021), Altered glycosylation of IgG4 promotes lectin complement pathway activation in anti-PLA2R1–associated membranous nephropathy, in Journal of Clinical Investigation, 131(5), 131(5):e14.
Renal AAV2-Mediated Overexpression of Long Non-Coding RNA H19 Attenuates Ischemic Acute Kidney Injury Through Sponging of microRNA-30a-5p
Haddad George, Kölling Malte, Wegmann Urs A., Dettling Angela, Seeger Harald, Schmitt Roland, Soerensen-Zender Inga, Haller Hermann, Kistler Andreas D., Dueck Anne, Engelhardt Stefan, Thum Thomas, Mueller Thomas F., Wüthrich Rudolf P., Lorenzen Johan M. (2021), Renal AAV2-Mediated Overexpression of Long Non-Coding RNA H19 Attenuates Ischemic Acute Kidney Injury Through Sponging of microRNA-30a-5p, in Journal of the American Society of Nephrology, 32(2), 323-341.
Collagen IVα345 dysfunction in glomerular basement membrane diseases. I. Discovery of a COL4A3 variant in familial Goodpasture’s and Alport diseases
Pokidysheva Elena N., Seeger Harald, Pedchenko Vadim, Chetyrkin Sergei, Bergmann Carsten, Abrahamson Dale, Cui Zhao Wei, Delpire Eric, Fervenza Fernando C., Fidler Aaron L., Fogo Agnes B., Gaspert Ariana, Grohmann Maik, Gross Oliver, Haddad George, Harris Raymond C., Kashtan Clifford, Kitching A. Richard, Lorenzen Johan M., McAdoo Stephen, Pusey Charles D., Segelmark Marten, Simmons Alicia, Voziyan Paul A., et al. (2021), Collagen IVα345 dysfunction in glomerular basement membrane diseases. I. Discovery of a COL4A3 variant in familial Goodpasture’s and Alport diseases, in Journal of Biological Chemistry, 296, 100590-100590.
Spectrum and dosing of urate-lowering drugs in a large cohort of chronic kidney disease patients and their effect on serum urate levels: a cross-sectional analysis from the German Chronic Kidney Disease study
Kielstein Jan T, Heisterkamp Markus, Jing Jiaojiao, Nadal Jennifer, Schmid Matthias, Kronenberg Florian, Busch Martin, Sommerer Claudia, Lorenzen Johan M, Eckardt Kai-Uwe, Köttgen Anna (2021), Spectrum and dosing of urate-lowering drugs in a large cohort of chronic kidney disease patients and their effect on serum urate levels: a cross-sectional analysis from the German Chronic Kidney Disease study, in Clinical Kidney Journal, 14(1), 277-283.
MALAT1: a therapeutic candidate for a broad spectrum of vascular and cardiorenal complications
Puthanveetil Prasanth, Gutschner Tony, Lorenzen Johan (2020), MALAT1: a therapeutic candidate for a broad spectrum of vascular and cardiorenal complications, in Hypertension Research, 43(5), 372-379.
Diagnostic and Therapeutic Potential of microRNAs in Acute Kidney Injury
Brandenburger Timo, Lorenzen Johan M. (2020), Diagnostic and Therapeutic Potential of microRNAs in Acute Kidney Injury, in Frontiers in Pharmacology, 11, 657.
Circular RNAs as non-invasive urinary biomarker of kidney diseases
Kölling Malte, Lorenzen Johan M. (2020), Circular RNAs as non-invasive urinary biomarker of kidney diseases, in Annals of Translational Medicine, 8(5), 255-255.
Circular RNAs in Urine of Kidney Transplant Patients with Acute T Cell-Mediated Allograft Rejection
Kölling Malte, Haddad George, Wegmann Urs, Kistler Andreas, Bosakova Andrea, Seeger Harald, Hübel Kerstin, Haller Hermann, Mueller Thomas, Wüthrich Rudolf P, Lorenzen Johan M (2019), Circular RNAs in Urine of Kidney Transplant Patients with Acute T Cell-Mediated Allograft Rejection, in Clinical Chemistry, 65(10), 1287-1294.
MicroRNA expression studies: challenge of selecting reliable reference controls for data normalization
Madadi Soheil, Schwarzenbach Heidi, Lorenzen Johan, Soleimani Meysam (2019), MicroRNA expression studies: challenge of selecting reliable reference controls for data normalization, in Cellular and Molecular Life Sciences, 76(18), 3497-3514.
Biogenesis and Function of Circular RNAs in Health and in Disease
Haddad George, Lorenzen Johan M. (2019), Biogenesis and Function of Circular RNAs in Health and in Disease, in Frontiers in Pharmacology, 10, 428.
Identification of cell and disease specific microRNAs in glomerular pathologies
Müller‐Deile Janina, Dannenberg Jan, Liu Peidi, Lorenzen Johan, Nyström Jenny, Thum Thomas, Schiffer Mario (2019), Identification of cell and disease specific microRNAs in glomerular pathologies, in Journal of Cellular and Molecular Medicine, 23(6), 3927-3939.
The hypoxic kidney: pathogenesis and noncoding RNA-based therapeutic strategies
Haddad George, Kölling Malte, Lorenzen Johan M. (2019), The hypoxic kidney: pathogenesis and noncoding RNA-based therapeutic strategies, in Swiss Medical Weekly, 149:w14703.
Large expert-curated database for benchmarking document similarity detection in biomedical literature search
Brown Peter, Tan Aik-Choon, El-Esawi Mohamed A, Liehr Thomas, Blanck Oliver, Gladue Douglas P, Almeida Gabriel M F, Cernava Tomislav, Sorzano Carlos O, Yeung Andy W K, Engel Michael S, Chandrasekaran Arun Richard, Muth Thilo, Staege Martin S, Daulatabad Swapna V, Widera Darius, Zhang Junpeng, Meule Adrian, Honjo Ken, Pourret Olivier, Yin Cong-Cong, Zhang Zhongheng, Cascella Marco, Flegel Willy A, et al. (2019), Large expert-curated database for benchmarking document similarity detection in biomedical literature search, in Database, 2019, 2019:baz08.
Hypoxia-induced long non-coding RNA Malat1 is dispensable for renal ischemia/reperfusion-injury
Kölling Malte, Genschel Celina, Kaucsar Tamas, Hübner Anika, Rong Song, Schmitt Roland, Sörensen-Zender Inga, Haddad George, Kistler Andreas, Seeger Harald, Kielstein Jan T., Fliser Danilo, Haller Hermann, Wüthrich Rudolf, Zörnig Martin, Thum Thomas, Lorenzen Johan (2018), Hypoxia-induced long non-coding RNA Malat1 is dispensable for renal ischemia/reperfusion-injury, in Scientific Reports, 8(1), 3438-3438.
Noncoding RNAs in acute kidney injury
Brandenburger Timo, Salgado Somoza Antonio, Devaux Yvan, Lorenzen Johan M. (2018), Noncoding RNAs in acute kidney injury, in Kidney International, 94(5), 870-881.
The Circular RNA ciRs-126 Predicts Survival in Critically Ill Patients With Acute Kidney Injury
Kölling Malte, Seeger Harald, Haddad George, Kistler Andreas, Nowak Albina, Faulhaber-Walter Robert, Kielstein Jan, Haller Hermann, Fliser Danilo, Mueller Thomas, Wüthrich Rudolf P., Lorenzen Johan M. (2018), The Circular RNA ciRs-126 Predicts Survival in Critically Ill Patients With Acute Kidney Injury, in Kidney International Reports, 3(5), 1144-1152.

Scientific events



Self-organised

Title Date Place
Symposium Akutes Nierenversagen der Universität Zürich 03.10.2018 Zürich, Switzerland

Awards

Title Year
Bernd Tersteegen Preis der Deutschen Nierenzentren e.V. 2018
Georg-Friedrich-Götz Preis der Universität Zürich 2018

Abstract

Renal fibrosis is commonly associated with various etiologies of chronic kidney disease. Its progression is a major determinant of end-stage renal disease. The cellular origin of matrix-producing cells of the kidney has been a matter of debate. Recently, it was shown in elegant fate-tracing experiments, that CD73+/platelet-derived growth factor receptor ß+ (PDGFR-ß) pericytes, are the major source of matrix-producing cells in the kidney. The mechanisms driving pericyte-to-myofibroblast transition are not fully elucidated. Non-coding RNAs might be important regulators of this process. Long non-coding RNAs (lncRNAs) are novel important epigenetic regulators of cellular function through various mechanisms, including the regulation of chromatin architecture, binding of protein and microRNA and directing of transcription factors to their sites of action. The overall aim of our proposal is to provide an in-depth analysis of lncRNA deregulation in isolated CD73+/PDGFR-ß+ cells as well as their function and therapeutic potential regarding fibrosis development in established murine models of kidney fibrosis and human kidney biopsies using state of the art molecular biology techniques. To this end we isolated and characterized CD73+/PDGFR-ß+-cells from mouse kidneys in an angiotensin II - induced kidney fibrosis model in preliminary experiments. Subsequently, isolated RNA of CD73+/PDGFR-ß+ cells was subjected to global lncRNA expression profiling. The antisense lncRNA X was among the most highly upregulated candidates. The following specific aims will be addressed:1.To analyse lncRNA X antisense transcript expression in renal biopsies of patients with various etiologies of chronic kidney disease to understand its regulation in human kidney diseases.2.To develop a novel lncRNA X (see below) - based therapeutic approach to ameliorate fibrosis development in 2 established fibrosis models: Ang II-induced fibrosis and renal fibrosis related to unilateral ureteral obstruction 3.To investigate the mechanistic role of lncRNA X in vitro and to determine its upstream transcriptional regulators and downstream target genes mediating pathological signalling. The role of the lncRNA X in promoting a phenotypic switch in pericyte-to- myofibroblast transdifferentiation, thereby resulting in fibrosis development, will be investigated. LncRNA X expresses several binding sites for microRNAs, thereby functioning as a microRNA sponge. Interestingly, our microRNA of interest is known to bioinformatically target several regulators of fibroblast activation. The lncRNA-microRNA interaction as well as regulation of target genes will be investigated in vitro and in vivo. In addition, lncRNA X shuttling into small vesicles will be assessed. Our analyses will provide important insights into the mechanisms driving pericyte-to-myofibroblast transition and may result in improved therapy of patients with chronic fibrotic kidney disease.
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