Abstract
Some aspects of renal physiology, in particular transport across tubular epithelia, are highly relevant to pharmacokinetics and to drug toxicity. The use of animals to model human renal physiology is limited, but human-derived renal organoids offer an alternative, relevant system in culture. Here, we explain how the activity of specific transport systems can be assessed in renal organoid and organ culture, using a system illustrated mainly for mouse but that can be extended to human organoids.
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References
Saxen L (1987) Organogenesis of the kidney. Cambridge University Press, Cambridge
Saxén L, Vainio T, Toivonen S (1962) Effect of polyoma virus on mouse kidney rudiment in vitro. J Natl Cancer Inst 29:597–631. https://doi.org/10.1093/jnci/29.3.597
Saxen L (1983) In vitro model-systems for chemical teratogenesis. In: Kolber A, Wong T, Grant L et al (eds) In vitro toxicity testing of environmental agents, part B. Plenum Press, New York, pp 173–190
Gorboulev V, Ulzheimer JC, Akhoundova A et al (1997) Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol 16:871–881
Karbach U, Kricke J, Meyer-Wentrup F et al (2000) Localization of organic cation transporters OCT1 and OCT2 in rat kidney. Am J Physiol Ren Physiol 279:F679–F687
Knight A (2008) Systematic reviews of animal experiments demonstrate poor contributions toward human healthcare. Rev Recent Clin Trials 3:89–96
Loghman-Adham M, Kiu Weber CI, Ciorciaro C et al (2012) Detection and management of nephrotoxicity during drug development. Expert Opin Drug Saf 11:581–596. https://doi.org/10.1517/14740338.2012.691964
Benjamin A, da Costa AN, Delaunois A et al (2015) Renal safety pharmacology in drug discovery and development. In: Handbook of experimental pharmacology. Springer, New York, pp 323–352
Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676. https://doi.org/10.1016/j.cell.2006.07.024
Davies J (2014) Engineered renal tissue as a potential platform for pharmacokinetic and nephrotoxicity testing. Drug Discov Today 19:725–729. https://doi.org/10.1016/j.drudis.2013.10.023
Amorino GP, Fox MH (1995) Intracellular Na+ measurements using sodium green tetraacetate with flow cytometry. Cytometry 21:248–256. https://doi.org/10.1002/cyto.990210305
Yasujima T, Ohta K, Inoue K, Yuasa H (2011) Characterization of human OCT1-mediated transport of DAPI as a fluorescent probe substrate. J Pharm Sci 100:4006–4012. https://doi.org/10.1002/jps.22548
Ichida K, Hosoyamada M, Kimura H et al (2003) Urate transport via human PAH transporter hOAT1 and its gene structure. Kidney Int 63:143–155. https://doi.org/10.1046/j.1523-1755.2003.00710.x
Monien BH, Müller C, Bakhiya N et al (2009) Probenecid, an inhibitor of transmembrane organic anion transporters, alters tissue distribution of DNA adducts in 1-hydroxymethylpyrene-treated rats. Toxicology 262:80–85. https://doi.org/10.1016/j.tox.2009.05.016
Schulz K, Hagos Y, Burckhardt G et al (2015) The isoquinolone derived prolyl hydroxylase inhibitor ICA is a potent substrate of the organic anion transporters 1 and 3. Nephron 131:285–289. https://doi.org/10.1159/000442531
Whitley AC, Sweet DH, Walle T (2005) The dietary polyphenol ellagic acid is a potent inhibitor of hOAT1. Drug Metab Dispos 33:1097–1100. https://doi.org/10.1124/dmd.105.004275
Enomoto A, Takeda M, Shimoda M et al (2002) Interaction of human organic anion transporters 2 and 4 with organic anion transport inhibitors. J Pharmacol Exp Ther 301:797–802
Shen H, Liu T, Morse BL et al (2015) Characterization of organic anion transporter 2 (SLC22A7): a highly efficient transporter for creatinine and species-dependent renal tubular expression. Drug Metab Dispos 43:984–993. https://doi.org/10.1124/dmd.114.062364
Hagos FT, Daood MJ, Ocque JA et al (2017) Probenecid, an organic anion transporter 1 and 3 inhibitor, increases plasma and brain exposure of N-acetylcysteine. Xenobiotica 47:346–353. https://doi.org/10.1080/00498254.2016.1187777
Hagos Y, Stein D, Ugele B et al (2007) Human renal organic anion transporter 4 operates as an asymmetric urate transporter. J Am Soc Nephrol 18:430–439. https://doi.org/10.1681/ASN.2006040415
Youngblood GL, Sweet DH (2004) Identification and functional assessment of the novel murine organic anion transporter Oat5 (Slc22a19) expressed in kidney. Am J Physiol Renal Physiol 287:F236–F244. https://doi.org/10.1152/ajprenal.00012.2004
Tan PK, Ostertag TM, Miner JN (2016) Mechanism of high affinity inhibition of the human urate transporter URAT1. Sci Rep 6:34995. https://doi.org/10.1038/srep34995
Gollapudi S, Kim C, Tran B et al (1997) Probenecid reverses multidrug resistance in mutidrug resistance-associated prtoein-overexpressing HL60/AR and H69/AR cells but not in P-glycoprotein-overexpressing HL60/Tax and P388/ADR cells. Cancer Chemother Pharmacol 40:150–158
Bakos E, Evers R, Sinkó E et al (2000) Interactions of the human multidrug resistance proteins MRP1 and MRP2 with organic anions. Mol Pharmacol 57:760–768
Gekeler V, Ise W, Sanders KH et al (1995) The leukotriene LTD4 receptor antagonist MK571 specifically modulates MRP associated multidrug resistance. Biochem Biophys Res Commun 208:345–352. https://doi.org/10.1006/bbrc.1995.1344
Zhang L, Schaner ME, Giacomini KM (1998) Functional characterization of an organic cation transporter (hOCT1) in a transiently transfected human cell line (HeLa). J Pharmacol Exp Ther 286:354–361
Okuda M, Saito H, Urakami Y et al (1996) cDNA cloning and functional expression of a novel rat kidney organic cation transporter, OCT2. Biochem Biophys Res Commun 224:500–507
Shu Y, Bello CL, Mangravite LM et al (2001) Functional characteristics and steroid hormone-mediated regulation of an organic cation transporter in Madin-Darby canine kidney cells. J Pharmacol Exp Ther 299:392–398
Kimura N, Masuda S, Tanihara Y et al (2005) Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. Drug Metab Pharmacokinet 20:379–386
Çetinkaya I, Ciarimboli G, Yalçinkaya G et al (2003) Regulation of human organic cation transporter hOCT2 by PKA, PI3K, and calmodulin-dependent kinases. Am J Physiol Renal Physiol 284:F293–F302. https://doi.org/10.1152/AJPRENAL.00251.2002
Ito S, Kusuhara H, Yokochi M et al (2012) Competitive inhibition of the luminal efflux by multidrug and toxin extrusions, but not basolateral uptake by organic cation transporter 2, is the likely mechanism underlying the pharmacokinetic drug-drug interactions caused by cimetidine in the kidney. J Pharmacol Exp Ther 340:393–403. https://doi.org/10.1124/jpet.111.184986
Hyafil F, Vergely C, Du Vignaud P, Grand-Perret T (1993) In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative. Cancer Res 53:4595–4602
Tai HL (2000) Technology evaluation: Valspodar, Novartis AG. Curr Opin Mol Ther 2:459–467
Kruijtzer CMF, Beijnen JH, Rosing H et al (2002) Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. J Clin Oncol 20:2943–2950. https://doi.org/10.1200/JCO.2002.12.116
Allen JD, van Loevezijn A, Lakhai JM et al (2002) Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C. Mol Cancer Ther 1:417–425
Wu W, Baker ME, Eraly SA et al (2009) Analysis of a large cluster of SLC22 transporter genes, including novel USTs, reveals species-specific amplification of subsets of family members. Physiol Genomics 38:116–124. https://doi.org/10.1152/physiolgenomics.90309.2008
Lickteig AJ, Cheng X, Augustine LM et al (2008) Tissue distribution, ontogeny and induction of the transporters Multidrug and toxin extrusion (MATE) 1 and MATE2 mRNA expression levels in mice. Life Sci 83:59–64. https://doi.org/10.1016/j.lfs.2008.05.004
Masuda S, Terada T, Yonezawa A et al (2006) Identification and functional characterization of a new human kidney-specific H+/organic cation antiporter, kidney-specific multidrug and toxin extrusion 2. J Am Soc Nephrol 17:2127–2135. https://doi.org/10.1681/ASN.2006030205
Harding SD, Sharman JL, Faccenda E et al (2018) The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY. Nucleic Acids Res. https://doi.org/10.1093/nar/gkx1121
Lawrence ML, Chang C-H, Davies JA (2015) Transport of organic anions and cations in murine embryonic kidney development and in serially-reaggregated engineered kidneys. Sci Rep 5:9092. https://doi.org/10.1038/srep09092
Sebinger DDR, Unbekandt M, Ganeva VV et al (2010) A novel, low-volume method for organ culture of embryonic kidneys that allows development of cortico-medullary anatomical organization. PLoS One 5:e10550. https://doi.org/10.1371/journal.pone.0010550
Takasato M, Er PX, Chiu HS et al (2015) Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature 526:564–568. https://doi.org/10.1038/nature15695
Tsuda M, Terada T, Mizuno T et al (2009) Targeted disruption of the multidrug and toxin extrusion 1 (Mate1) gene in mice reduces renal secretion of metformin. Mol Pharmacol 75:1280–1286. https://doi.org/10.1124/mol.109.056242
Matsushima S, Maeda K, Inoue K et al (2009) The inhibition of human multidrug and toxin extrusion 1 is involved in the drug-drug interaction caused by cimetidine. Drug Metab Dispos 37:555–559. https://doi.org/10.1124/dmd.108.023911
Ciarimboli G, Deuster D, Knief A et al (2010) Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions. Am J Pathol 176:1169–1180. https://doi.org/10.2353/ajpath.2010.090610
Yasujima T, Ohta K-y, Inoue K et al (2010) Evaluation of 4′,6-diamidino-2-phenylindole as a fluorescent probe substrate for rapid assays of the functionality of human multidrug and toxin extrusion proteins. Drug Metab Dispos 38:715–721. https://doi.org/10.1124/dmd.109.030221
Wilmer MJ, Saleem MA, Masereeuw R et al (2010) Novel conditionally immortalized human proximal tubule cell line expressing functional influx and efflux transporters. Cell Tissue Res 339:449–457. https://doi.org/10.1007/s00441-009-0882-y
Kruh GD, Belinsky MG (2003) The MRP family of drug efflux pumps. Oncogene 22:7537–7552. https://doi.org/10.1038/sj.onc.1206953
Allikmets R, Schriml LM, Hutchinson A et al (1998) A human placenta-specific ATP-binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance. Cancer Res 58:5337–5339
Wang RB, Kuo CL, Lien LL, Lien EJ (2003) Structure-activity relationship: analyses of p-glycoprotein substrates and inhibitors. J Clin Pharm Ther 28:203–228. https://doi.org/10.1046/j.1365-2710.2003.00487.x
Mikkaichi T, Suzuki T, Onogawa T et al (2004) Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney. Proc Natl Acad Sci U S A 101:3569–3574. https://doi.org/10.1073/pnas.0304987101
Hughes J, Crowe A (2010) Inhibition of P-glycoprotein-mediated efflux of digoxin and its metabolites by macrolide antibiotics. J Pharmacol Sci 113:315–324
Pavek P, Merino G, Wagenaar E et al (2005) Human breast cancer resistance protein: interactions with steroid drugs, hormones, the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and transport of cimetidine. J Pharmacol Exp Ther 312:144–152. https://doi.org/10.1124/jpet.104.073916
Morozova GI, Dobretsov GE, Dubur GI et al (1981) 4-(n-Dimethylaminostyryl)-1-methylpyridinium fluorescence in a living cell. Tsitologiia 23:916–923
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Lawrence, M.L., Elhendawi, M., Davies, J.A. (2019). Investigating Aspects of Renal Physiology and Pharmacology in Organ and Organoid Culture. In: Vainio, S. (eds) Kidney Organogenesis. Methods in Molecular Biology, vol 1926. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-9021-4_11
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DOI: https://doi.org/10.1007/978-1-4939-9021-4_11
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