title: Development and Application of Human Renal Proximal Tubule Epithelial Cells for Assessment of Compound Toxicity.
abstract: Kidney toxicity is a major problem both in drug development and clinical settings. It is difficult to predict nephrotoxicity in part because of the lack of appropriatein vitrocell models, limited endpoints, and the observation that the activity of membrane transporters which plays important roles in nephrotoxicity by affecting the pharmacokinetic profile of drugs is often not taken into account. We developed a new cell model using pseudo-immortalized human primary renal proximal tubule epithelial cells. This cell line (SA7K) was characterized by the presence of proximal tubule cell markers as well as several functional properties, including transporter activity and response to a few well-characterized nephrotoxicants. We subsequently evaluated a group of potential nephrotoxic compounds in SA7K cells and compared them to a commonly used human immortalized kidney cell line (HK-2). Cells were treated with test compounds and three endpoints were analyzed, including cell viability, apoptosis and mitochondrial membrane potential. The results showed that most of the known nephrotoxic compounds could be detected in one or more of these endpoints. There were sensitivity differences in response to several of the chemicals between HK-2 and SA7K cells, which may relate to differences in expressions of key transporters or other components of nephrotoxicity pathways. Our data suggest that SA7K cells appear as promising for the early detection of renal toxicants.
authors.affiliation: 9800 Medical Center Drive, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892-3375, USA.
authors.forename: Shuaizhang
authors.initials: S
authors.lastname: Li
authors.affiliation: 9800 Medical Center Drive, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892-3375, USA.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Zhao
authors.affiliation: 9800 Medical Center Drive, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892-3375, USA.
authors.forename: Ruili
authors.initials: R
authors.lastname: Huang
authors.affiliation: Sigma-Aldrich Corporation, St. Louis, MO 63103, USA.
authors.forename: Toni
authors.initials: T
authors.lastname: Steiner
authors.affiliation: Sigma-Aldrich Corporation, St. Louis, MO 63103, USA.
authors.forename: Maureen
authors.initials: M
authors.lastname: Bourner
authors.affiliation: Sigma-Aldrich Corporation, St. Louis, MO 63103, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Mitchell
authors.affiliation: Sigma-Aldrich Corporation, St. Louis, MO 63103, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Thompson
authors.affiliation: Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 10085, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.affiliation: 9800 Medical Center Drive, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892-3375, USA.
authors.forename: Menghang
authors.initials: M
authors.lastname: Xia
keywords: Apoptosis; Mitochondrial membrane potential (MMP); Nephrotoxicity; SA7K cells; Transporters