Advertisement

Precision-cut human kidney slices as a model to elucidate the process of renal fibrosis

  • Elisabeth G.D. Stribos
    Affiliations
    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
    Search for articles by this author
  • Theerut Luangmonkong
    Affiliations
    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
    Search for articles by this author
  • Anna M. Leliveld
    Affiliations
    Department of Urology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
    Search for articles by this author
  • Igle J. de Jong
    Affiliations
    Department of Urology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
    Search for articles by this author
  • Willem J. van Son
    Affiliations
    Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
    Search for articles by this author
  • Jan-Luuk Hillebrands
    Affiliations
    Division of Pathology, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
    Search for articles by this author
  • Marc A. Seelen
    Affiliations
    Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
    Search for articles by this author
  • Harry van Goor
    Affiliations
    Division of Pathology, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
    Search for articles by this author
  • Peter Olinga
    Correspondence
    Reprint requests: Peter Olinga, Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
    Affiliations
    Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
    Search for articles by this author
  • Henricus A.M. Mutsaers
    Affiliations
    Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
    Search for articles by this author
Published:November 25, 2015DOI:https://doi.org/10.1016/j.trsl.2015.11.007
      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.

      Abbreviations:

      ATP (adenosine triphosphate), BCRP (breast cancer resistance protein), CKD (chronic kidney disease), COL1A1 (collagen type 1A1), ECM (extracellular matrix), ESRD (end-stage renal disease), FN1 (fibronectin 1), GAPDH (glyceraldehyde 3-phosphate dehydrogenase), 7-HCG (7-hydroxycoumarin glucuronide), HPLC (high-performance liquid chromatography), HSP47 (heat shock protein 47), LDH (lactate dehydrogenase), OAT (organic anion transporter), OATP4C1 (organic anion transporting polypeptide 4C1), PAI (plasminogen activator inhibitor), PAS (Periodic acid–Schiff), PCKSs (precision-cut kidney slices), PDGFB (platelet-derived growth factor subunit B), qPCR (quantitative real-time polymerase chain reaction), TGF-β1 (transforming growth factor β1), UGT (Uridine 5'-diphospho-glucuronosyltransferase), α-SMA (α-smooth muscle actin)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • James M.T.
        • Hemmelgarn B.R.
        • Tonelli M.
        Early recognition and prevention of chronic kidney disease.
        Lancet. 2010; 375: 1296-1309
        • Decleves A.E.
        • Sharma K.
        Novel targets of antifibrotic and anti-inflammatory treatment in CKD.
        Nat Rev Nephrol. 2014; 10: 257-267
        • Lee S.Y.
        • Kim S.I.
        • Choi M.E.
        Therapeutic targets for treating fibrotic kidney diseases.
        Transl Res. 2015; 165: 512-530
        • Rockey D.C.
        • Bell P.D.
        • Hill J.A.
        Fibrosis—a common pathway to organ injury and failure.
        N Engl J Med. 2015; 372: 1138-1149
        • Cernaro V.
        • Trifiro G.
        • Lorenzano G.
        • et al.
        New therapeutic strategies under development to halt the progression of renal failure.
        Expert Opin Investig Drugs. 2014; 23: 693-709
        • Mutsaers H.A.M.
        • Stribos E.G.D.
        • Glorieux G.
        • et al.
        Chronic kidney disease and fibrosis: the role of uremic retention solutes.
        Front Med. 2015; 2: 60
        • Eddy A.A.
        • Fogo A.B.
        Plasminogen activator inhibitor-1 in chronic kidney disease: evidence and mechanisms of action.
        J Am Soc Nephrol. 2006; 17: 2999-3012
        • Inoue T.
        • Umezawa A.
        • Takenaka T.
        • et al.
        The contribution of epithelial-mesenchymal transition to renal fibrosis differs among kidney disease models.
        Kidney Int. 2015; 87: 233-238
        • Poosti F.
        • Pham B.T.
        • Oosterhuis D.
        • et al.
        Precision-cut kidney slices (PCKS) to study development of renal fibrosis and efficacy of drug targeting ex vivo.
        Dis Model Mech. 2015; 18: 1227-1236
        • de Graaf I.A.
        • Olinga P.
        • de Jager M.H.
        • et al.
        Preparation and incubation of precision-cut liver and intestinal slices for application in drug metabolism and toxicity studies.
        Nat Protoc. 2010; 5: 1540-1551
        • Westra I.M.
        • Oosterhuis D.
        • Groothuis G.M.
        • et al.
        Precision-cut liver slices as a model for the early onset of liver fibrosis to test antifibrotic drugs.
        Toxicol Appl Pharmacol. 2014; 274: 328-338
        • De Kanter R.
        • De Jager M.H.
        • Draaisma A.L.
        • et al.
        Drug-metabolizing activity of human and rat liver, lung, kidney and intestine slices.
        Xenobiotica. 2002; 32: 349-362
        • van de Bovenkamp M.
        • Groothuis G.M.
        • Meijer D.K.
        • et al.
        Liver slices as a model to study fibrogenesis and test the effects of anti-fibrotic drugs on fibrogenic cells in human liver.
        Toxicol In Vitro. 2008; 22: 771-778
        • Mutsaers H.A.
        • Wilmer M.J.
        • Reijnders D.
        • et al.
        Uremic toxins inhibit renal metabolic capacity through interference with glucuronidation and mitochondrial respiration.
        Biochim Biophys Acta. 2013; 1832: 142-150
        • Nomura M.
        • Motohashi H.
        • Sekine H.
        • et al.
        Developmental expression of renal organic anion transporters in rat kidney and its effect on renal secretion of phenolsulfonphthalein.
        Am J Physiol Renal Physiol. 2012; 302: F1640-F1649
        • Brown C.D.
        • Sayer R.
        • Windass A.S.
        • et al.
        Characterisation of human tubular cell monolayers as a model of proximal tubular xenobiotic handling.
        Toxicol Appl Pharmacol. 2008; 233: 428-438
        • Margaillan G.
        • Rouleau M.
        • Fallon J.K.
        • et al.
        Quantitative profiling of human renal UDP-glucuronosyltransferases and glucuronidation activity: a comparison of normal and tumoral kidney tissues.
        Drug Metab Dispos. 2015; 43: 611-619
        • Pusztaszeri M.P.
        • Seelentag W.
        • Bosman F.T.
        Immunohistochemical expression of endothelial markers CD31, CD34, von Willebrand factor, and Fli-1 in normal human tissues.
        J Histochem Cytochem. 2006; 54: 385-395
        • Zeisberg E.M.
        • Potenta S.E.
        • Sugimoto H.
        • et al.
        Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition.
        J Am Soc Nephrol. 2008; 19: 2282-2287
        • Herman-Edelstein M.
        • Thomas M.C.
        • Thallas-Bonke V.
        • et al.
        Dedifferentiation of immortalized human podocytes in response to transforming growth factor-beta: a model for diabetic podocytopathy.
        Diabetes. 2011; 60: 1779-1788
        • van Roeyen C.R.
        • Eitner F.
        • Boor P.
        • et al.
        Induction of progressive glomerulonephritis by podocyte-specific overexpression of platelet-derived growth factor-D.
        Kidney Int. 2011; 80: 1292-1305
        • Miceli I.
        • Burt D.
        • Tarabra E.
        • et al.
        Stretch reduces nephrin expression via an angiotensin II-AT(1)-dependent mechanism in human podocytes: effect of rosiglitazone.
        Am J Physiol Renal Physiol. 2010; 298: F381-F390
        • Hinz B.
        The myofibroblast: paradigm for a mechanically active cell.
        J Biomech. 2010; 43: 146-155
        • Strutz F.
        • Zeisberg M.
        Renal fibroblasts and myofibroblasts in chronic kidney disease.
        J Am Soc Nephrol. 2006; 17: 2992-2998
        • Border W.A.
        • Noble N.A.
        Transforming growth factor beta in tissue fibrosis.
        N Engl J Med. 1994; 331: 1286-1292
        • Eddy A.A.
        Overview of the cellular and molecular basis of kidney fibrosis.
        Kidney Int Suppl (2011). 2014; 4: 2-8
        • Lin S.L.
        • Castano A.P.
        • Nowlin B.T.
        • et al.
        Bone marrow Ly6Chigh monocytes are selectively recruited to injured kidney and differentiate into functionally distinct populations.
        J Immunol. 2009; 183: 6733-6743