title: Precision-cut human kidney slices as a model to elucidate the process of renal fibrosis.
abstract: Chronic kidney disease is a major health concern, and experimental models bridging the gap between animal studies and clinical research are currently lacking. Here, we evaluated precision-cut kidney slices (PCKSs) as a potential model for renal disease. PCKSs were prepared from human cortical tissue obtained from tumor nephrectomies and cultured up to 96 hours. Morphology, cell viability, and metabolic functionality (ie, uridine 5'-diphospho-glucuronosyltransferase and transporter activity) were determined to assess the integrity of PCKSs. Furthermore, inflammatory and fibrosis-related gene expressions were characterized. Finally, to validate the model, renal fibrogenesis was induced using transforming growth factor β1 (TGF-β1). Preparation of PCKSs induced an inflammatory tissue response, whereas long-term incubation (96 hours) induced fibrogenesis as shown by an increased expression of collagen type 1A1 (COL1A1) and fibronectin 1 (FN1). Importantly, PCKSs remained functional for more than 48 hours as evidenced by active glucuronidation and phenolsulfonphthalein uptake. In addition, cellular diversity appeared to be maintained, yet we observed a clear loss of nephrin messenger RNA levels suggesting that our model might not be suitable to study the role of podocytes in renal pathology. Moreover, TGF-β1 exposure augmented fibrosis, as illustrated by an increased expression of multiple fibrosis markers including COL1A1, FN1, and α-smooth muscle actin. In conclusion, PCKSs maintain their renal phenotype during culture and appear to be a promising model to investigate renal diseases, for example, renal fibrosis. Moreover, the human origin of PCKSs makes this model very suitable for translational research.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands.
authors.forename: Elisabeth G D
authors.initials: EGD
authors.lastname: Stribos
authors.affiliation: Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands; Faculty of Pharmacy, Department of Pharmacology, Mahidol University, Bangkok, Thailand.
authors.forename: Theerut
authors.initials: T
authors.lastname: Luangmonkong
authors.affiliation: Department of Urology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Leliveld
authors.affiliation: Department of Urology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Igle J
authors.initials: IJ
authors.lastname: de Jong
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Willem J
authors.initials: WJ
authors.lastname: van Son
authors.affiliation: Division of Pathology, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Jan-Luuk
authors.initials: JL
authors.lastname: Hillebrands
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Seelen
authors.affiliation: Division of Pathology, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: van Goor
authors.affiliation: Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands. Electronic address: p.olinga@rug.nl.
authors.forename: Peter
authors.initials: P
authors.lastname: Olinga
authors.affiliation: Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands.
authors.forename: Henricus A M
authors.initials: HAM
authors.lastname: Mutsaers
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D005260:Female; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009924:Organ Culture Techniques / Q000379:methods*; D027362:Organic Anion Transport Protein 1 / Q000235:genetics / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D014468:Umbelliferones / Q000378:metabolism
chemical_list: D015415:Biomarkers; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D027362:Organic Anion Transport Protein 1; D027361:Organic Anion Transporters; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D016212:Transforming Growth Factor beta; D014468:Umbelliferones; C039928:7-hydroxycoumarin glucuronide; D000255:Adenosine Triphosphate