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Int. J. Mol. Sci. 2014, 15(11), 21348-21365; doi:10.3390/ijms151121348

Multigenerational Study of Chemically Induced Cytotoxicity and Proliferation in Cultures of Human Proximal Tubular Cells

Department of Pharmacology, Wayne State University School of Medicine, 540 East Canfield Avenue, Detroit, MI 48201, USA
Present address: Detroit R&D, 2727 Second Avenue, Detroit, MI 48201, USA
Present address: Center for Lung Biology and Baromedicine, Institute for Environmental Medicine, University of Pennsylvania Medical Center, 1 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104, USA.
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Author to whom correspondence should be addressed.
Received: 17 July 2014 / Revised: 24 October 2014 / Accepted: 7 November 2014 / Published: 18 November 2014
(This article belongs to the Special Issue Renal Toxicology—Epidemiology and Mechanisms)
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Abstract

Primary cultures of human proximal tubular (hPT) cells are a useful experimental model to study transport, metabolism, cytotoxicity, and effects on gene expression of a diverse array of drugs and environmental chemicals because they are derived directly from the in vivo human kidney. To extend the model to investigate longer-term processes, primary cultures (P0) were passaged for up to four generations (P1–P4). hPT cells retained epithelial morphology and stained positively for cytokeratins through P4, although cell growth and proliferation successively slowed with each passage. Necrotic cell death due to the model oxidants tert-butyl hydroperoxide (tBH) and methyl vinyl ketone (MVK) increased with increasing passage number, whereas that due to the selective nephrotoxicant S-(1,2-dichlorovinyl)-l-cysteine (DCVC) was modest and did not change with passage number. Mitochondrial activity was lower in P2–P4 cells than in either P0 or P1 cells. P1 and P2 cells were most sensitive to DCVC-induced apoptosis. DCVC also increased cell proliferation most prominently in P1 and P2 cells. Modest differences with respect to passage number and response to DCVC exposure were observed in expression of three key proteins (Hsp27, GADD153, p53) involved in stress response. Hence, although there are some modest differences in function with passage, these results support the use of multiple generations of hPT cells as an experimental model. View Full-Text
Keywords: human kidney; proximal tubular cells; primary cell culture; apoptosis; proliferation; stress response human kidney; proximal tubular cells; primary cell culture; apoptosis; proliferation; stress response
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Lash, L.H.; Putt, D.A.; Benipal, B. Multigenerational Study of Chemically Induced Cytotoxicity and Proliferation in Cultures of Human Proximal Tubular Cells. Int. J. Mol. Sci. 2014, 15, 21348-21365.

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