Sensitivity of Human Induced Pluripotent Stem Cells and Thereof Differentiated Kidney Proximal Tubular Cells Towards Selected Nephrotoxins

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Jan 11

PMID 38203251

Authors

Isaac Musong Mboni-Johnston

Nazih Mohamed Zakari Kouidrat

Cornelia Hirsch

Andreas Georg Weber

Alexander Meissner

James Adjaye

Nicole Schupp

Affiliations

Soon will be listed here.

Abstract

Proximal tubular epithelial cells (PTEC) are constantly exposed to potentially toxic metabolites and xenobiotics. The regenerative potential of the kidney enables the replacement of damaged cells either via the differentiation of stem cells or the re-acquisition of proliferative properties of the PTEC. Nevertheless, it is known that renal function declines, suggesting that the deteriorated cells are not replaced by fully functional cells. To understand the possible causes of this loss of kidney cell function, it is crucial to understand the role of toxins during the regeneration process. Therefore, we investigated the sensitivity and function of human induced pluripotent stem cells (hiPSC), hiPSC differentiating, and hiPSC differentiated into proximal tubular epithelial-like cells (PTELC) to known nephrotoxins. hiPSC were differentiated into PTELC, which exhibited similar morphology to PTEC, expressed prototypical PTEC markers, and were able to undergo albumin endocytosis. When treated with two nephrotoxins, hiPSC and differentiating hiPSC were more sensitive to cisplatin than differentiated PTELC, whereas all stages were equally sensitive to cyclosporin A. Both toxins also had an inhibitory effect on albumin uptake. Our results suggest a high sensitivity of differentiating cells towards toxins, which could have an unfavorable effect on regenerative processes. To study this, our model of hiPSC differentiating into PTELC appears suitable.

Citing Articles

Combined inhibition of RAD51 and CHK1 causes synergistic toxicity in cisplatin resistant cancer cells by triggering replication fork collapse.

Mann J, Niedermayer K, Krautstrunk J, Abbey L, Wiesmuller L, Piekorz R Int J Cancer. 2024; 156(2):389-402.

PMID: 39239809 PMC: 11578078. DOI: 10.1002/ijc.35164.

References

Wang M, Wang J, Tsui A, Li Z, Zhang Y, Zhao Q . Mechanisms of peripheral neurotoxicity associated with four chemotherapy drugs using human induced pluripotent stem cell-derived peripheral neurons. Toxicol In Vitro. 2021; 77:105233. DOI: 10.1016/j.tiv.2021.105233. View

Shitara Y, Takeuchi K, Nagamatsu Y, Wada S, Sugiyama Y, Horie T . Long-lasting inhibitory effects of cyclosporin A, but not tacrolimus, on OATP1B1- and OATP1B3-mediated uptake. Drug Metab Pharmacokinet. 2012; 27(4):368-78. DOI: 10.2133/dmpk.dmpk-11-rg-096. View

Valentich J, Tchao R, LEIGHTON J . Hemicyst formation stimulated by cyclic AMP in dog kidney cell line MDCK. J Cell Physiol. 1979; 100(2):291-304. DOI: 10.1002/jcp.1041000210. View

Lv Z, Xie G, Cui H, Yao Z, Shao C, Yuan W . Cyclosporin-A reduced the cytotoxicity of propranolol in HUVECs via p38 MAPK signaling. Medicine (Baltimore). 2022; 101(4):e28329. PMC: 8797567. DOI: 10.1097/MD.0000000000028329. View

Berger K, Moeller M . Mechanisms of epithelial repair and regeneration after acute kidney injury. Semin Nephrol. 2014; 34(4):394-403. DOI: 10.1016/j.semnephrol.2014.06.006. View

Hori Y, Aoki N, Kuwahara S, Hosojima M, Kaseda R, Goto S . Megalin Blockade with Cilastatin Suppresses Drug-Induced Nephrotoxicity. J Am Soc Nephrol. 2017; 28(6):1783-1791. PMC: 5461786. DOI: 10.1681/ASN.2016060606. View

OBrien J, Wilson I, Orton T, Pognan F . Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity. Eur J Biochem. 2000; 267(17):5421-6. DOI: 10.1046/j.1432-1327.2000.01606.x. View

Zou L, Stecula A, Gupta A, Prasad B, Chien H, Yee S . Molecular Mechanisms for Species Differences in Organic Anion Transporter 1, OAT1: Implications for Renal Drug Toxicity. Mol Pharmacol. 2018; 94(1):689-699. PMC: 5987998. DOI: 10.1124/mol.117.111153. View

Arjumand W, Seth A, Sultana S . Rutin attenuates cisplatin induced renal inflammation and apoptosis by reducing NFκB, TNF-α and caspase-3 expression in wistar rats. Food Chem Toxicol. 2011; 49(9):2013-21. DOI: 10.1016/j.fct.2011.05.012. View

10.

Afjal M, Goswami P, Ahmad S, Dabeer S, Akhter J, Salman M . Tempol (4-hydroxy tempo) protects mice from cisplatin-induced acute kidney injury modulation of expression of aquaporins and kidney injury molecule-1. Drug Chem Toxicol. 2020; 45(3):1355-1363. DOI: 10.1080/01480545.2020.1831011. View

11.

Chu X, Bleasby K, Evers R . Species differences in drug transporters and implications for translating preclinical findings to humans. Expert Opin Drug Metab Toxicol. 2012; 9(3):237-52. DOI: 10.1517/17425255.2013.741589. View

12.

Rangaswamy D, Sud K . Acute kidney injury and disease: Long-term consequences and management. Nephrology (Carlton). 2018; 23(11):969-980. DOI: 10.1111/nep.13408. View

13.

Kishore B, Krane C, Di Iulio D, Menon A, Cacini W . Expression of renal aquaporins 1, 2, and 3 in a rat model of cisplatin-induced polyuria. Kidney Int. 2000; 58(2):701-11. DOI: 10.1046/j.1523-1755.2000.00216.x. View

14.

Lim S, Ahn K, Sheen M, Jeon U, Kim J, Yang C . Downregulation of renal sodium transporters and tonicity-responsive enhancer binding protein by long-term treatment with cyclosporin A. J Am Soc Nephrol. 2007; 18(2):421-9. DOI: 10.1681/ASN.2006060664. View

15.

Wang T, Li N, Jin L, Qi X, Zhang C, Hua D . The calcium pump PMCA4 prevents epithelial-mesenchymal transition by inhibiting NFATc1-ZEB1 pathway in gastric cancer. Biochim Biophys Acta Mol Cell Res. 2020; 1867(12):118833. DOI: 10.1016/j.bbamcr.2020.118833. View

16.

Motohashi H, Katsura T, Saito H, Inui K . Effects of tacrolimus and cyclosporin A on peptide transporter PEPT1 in Caco-2 cells. Pharm Res. 2001; 18(5):713-7. DOI: 10.1023/a:1011006015593. View

17.

Schultze N, Wanka H, Zwicker P, Lindequist U, Haertel B . Mitochondrial functions of THP-1 monocytes following the exposure to selected natural compounds. Toxicology. 2016; 377:57-63. DOI: 10.1016/j.tox.2016.12.006. View

18.

Wing C, Komatsu M, Delaney S, Krause M, Wheeler H, Dolan M . Application of stem cell derived neuronal cells to evaluate neurotoxic chemotherapy. Stem Cell Res. 2017; 22:79-88. PMC: 5737666. DOI: 10.1016/j.scr.2017.06.006. View

19.

Tiong H, Huang P, Xiong S, Li Y, Vathsala A, Zink D . Drug-induced nephrotoxicity: clinical impact and preclinical in vitro models. Mol Pharm. 2014; 11(7):1933-48. DOI: 10.1021/mp400720w. View

20.

Yang Y, Liu H, Liu F, Dong Z . Mitochondrial dysregulation and protection in cisplatin nephrotoxicity. Arch Toxicol. 2014; 88(6):1249-56. PMC: 4274771. DOI: 10.1007/s00204-014-1239-1. View