Ex vivo studies of renal fibrosis: Insights into mechanisms and treatment targets

Elisabeth Godefrida Dieuwke Stribos

Ex vivo studies van nierfibrose: Insights into mechanisms and treatment targets

Elisabeth Godefrida Dieuwke Stribos

Farmaceutische Technologie en Biofarmacie

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Samenvatting

Overtollige littekenvorming in de nier, ook wel nierfibrose genoemd, ligt ten grondslag aan nierfunctieverlies bij patiënten met chronische nierziekte. Dit laatste wordt veroorzaakt door hoge bloeddruk, ontstekingen, schadelijke stoffen of medicijnen. Veel patiënten met chronische nierziekte ontwikkelen uiteindelijk eindstadium nierfalen, waarbij levensreddende therapieën zoals dialyse of een niertransplantatie nodig zijn.

Er bestaan op dit moment geen therapieën gericht op het voorkomen van fibrose om eindstadium nierfalen tegen te gaan. Helaas hebben veelbelovende geneesmiddelen, geïdentificeerd middels dierproeven, niet geleid tot succesvolle klinische studies in mensen. Er is daarom grote behoefte aan modellen die de effectiviteit van medicijnen in de mens kunnen voorspellen om de ontwikkeling van antifibrotische medicijnen te versnellen.

In haar proefschrift, deed Stribos onderzoek naar een nieuw experimenteel model, genaamd precision-cut kidney slices (PCKS), of makkelijker gezegd nierslices, een ex vivo model waarin alle celtypes van de nier aanwezig zijn.

De resultaten beschreven in dit proefschrift laten zien dat nierslices een veelbelovend model is om de pathogenese van nierfibrose te bestuderen, evenals om kennis te verkrijgen over geschikte ‘drug targets’ zoals tyrosine kinase receptoren en de transforming growth factor-β signaalroute. Ook heeft de nierslice techniek zich ontwikkeld tot een sterk translationeel model dankzij het gebruik van humane nierslices en draagt het bij aan het verminderen van proefdierenonderzoek. De resultaten beschreven in dit proefschrift bieden een goede fundering voor het ontwikkelen van nieuwe en effectieve therapieën voor nierfibrose.

Vertaalde titel van de bijdrage	Ex vivo studies van nierfibrose
Originele taal-2	English
Kwalificatie	Doctor of Philosophy
Toekennende instantie	Rijksuniversiteit Groningen
Begeleider(s)/adviseur	Olinga, Peter, Supervisor van Goor, Harry, Supervisor Seelen, Marcus, Co-supervisor Mutsaers, Rick, Co-supervisor
Datum van toekenning	11-dec-2017
Plaats van publicatie	[Groningen]
Uitgever	Rijksuniversiteit Groningen
Gedrukte ISBN's	978-94-034-0241-3
Elektronische ISBN's	978-94-034-0240-6
Status	Published - 2017

Toegang tot document

Title and contentsFinal publisher's version, 1,31 MB
Chapter 1Final publisher's version, 3,08 MB
Chapter 2Final publisher's version, 2,68 MB
Chapter 3Final publisher's version, 4,39 MB
Chapter 4Final publisher's version, 5,52 MB
Chapter 5Final publisher's version, 10,5 MB
Chapter 6Final publisher's version, 7,08 MB
Chapter 7Final publisher's version, 4,04 MB
Chapter 8Final publisher's version, 4,55 MB
Chapter 9Final publisher's version, 2,7 MB
Chapter 10Final publisher's version, 1,91 MB
Complete ThesisFinal publisher's version, 23,1 MB
PropositionsFinal publisher's version, 22,4 KB

Citeer dit

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title = "Ex vivo studies of renal fibrosis: Insights into mechanisms and treatment targets",

abstract = "Chronic kidney disease (CKD) is a condition characterized by progressive loss of renal function, often due to advancing scar formation (i.e. fibrosis). However, despite current treatment modalities, CKD can eventually progress to end-stage renal disease where patients are in need of renal replacement therapy (dialysis or renal transplantation). Therefore, novel treatment options are needed to impede or even reverse fibrogenesis in order to halt CKD progression.The development of novel antifibrotic therapies is being hampered by the lack of translational models that can predict drug efficacy in humans. Fortunately, as delineated in this thesis, precision-cut kidney slices (PCKS) could be the long-coveted translational model needed for drug development. This unique model encompasses all the different cells that constitute an organ and normal architecture is maintained allowing for cell-cell and cell-matrix interactions. The current body of work details the use of PCKS to unravel the pathophysiology of renal fibrogenesis, and in the identification of therapeutic targets. This thesis provides a detailed characterization of murine and human PCKS as a novel translational model of renal fibrosis, which can be used to study mechanisms of disease and to identify potential therapeutic targets such as tyrosine kinase receptors and the transforming growth factor-β pathway. In addition, the results delineated in this thesis will contribute to the reduction of animal experiments in the field of fibrosis research. PCKS are a great tool in the quest for antifibrotic therapies, which will immensely improve the quality of life of CKD patients.",

author = "Stribos, {Elisabeth Godefrida Dieuwke}",

year = "2017",

language = "English",

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N2 - Chronic kidney disease (CKD) is a condition characterized by progressive loss of renal function, often due to advancing scar formation (i.e. fibrosis). However, despite current treatment modalities, CKD can eventually progress to end-stage renal disease where patients are in need of renal replacement therapy (dialysis or renal transplantation). Therefore, novel treatment options are needed to impede or even reverse fibrogenesis in order to halt CKD progression.The development of novel antifibrotic therapies is being hampered by the lack of translational models that can predict drug efficacy in humans. Fortunately, as delineated in this thesis, precision-cut kidney slices (PCKS) could be the long-coveted translational model needed for drug development. This unique model encompasses all the different cells that constitute an organ and normal architecture is maintained allowing for cell-cell and cell-matrix interactions. The current body of work details the use of PCKS to unravel the pathophysiology of renal fibrogenesis, and in the identification of therapeutic targets. This thesis provides a detailed characterization of murine and human PCKS as a novel translational model of renal fibrosis, which can be used to study mechanisms of disease and to identify potential therapeutic targets such as tyrosine kinase receptors and the transforming growth factor-β pathway. In addition, the results delineated in this thesis will contribute to the reduction of animal experiments in the field of fibrosis research. PCKS are a great tool in the quest for antifibrotic therapies, which will immensely improve the quality of life of CKD patients.

AB - Chronic kidney disease (CKD) is a condition characterized by progressive loss of renal function, often due to advancing scar formation (i.e. fibrosis). However, despite current treatment modalities, CKD can eventually progress to end-stage renal disease where patients are in need of renal replacement therapy (dialysis or renal transplantation). Therefore, novel treatment options are needed to impede or even reverse fibrogenesis in order to halt CKD progression.The development of novel antifibrotic therapies is being hampered by the lack of translational models that can predict drug efficacy in humans. Fortunately, as delineated in this thesis, precision-cut kidney slices (PCKS) could be the long-coveted translational model needed for drug development. This unique model encompasses all the different cells that constitute an organ and normal architecture is maintained allowing for cell-cell and cell-matrix interactions. The current body of work details the use of PCKS to unravel the pathophysiology of renal fibrogenesis, and in the identification of therapeutic targets. This thesis provides a detailed characterization of murine and human PCKS as a novel translational model of renal fibrosis, which can be used to study mechanisms of disease and to identify potential therapeutic targets such as tyrosine kinase receptors and the transforming growth factor-β pathway. In addition, the results delineated in this thesis will contribute to the reduction of animal experiments in the field of fibrosis research. PCKS are a great tool in the quest for antifibrotic therapies, which will immensely improve the quality of life of CKD patients.

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