title: Comparison of changes in urinary and blood levels of biomarkers associated with proximal tubular injury in rat models.
abstract: To investigate useful biomarkers associated with proximal tubular injury, we assessed changes in levels of a focused set of biomarkers in urine and blood. Male rats administered a single dose or four doses of gentamicin (GM, 240 mg/kg/day) or a single dose of cisplatin (CDDP, 5 mg/kg) were euthanized on days 2 (the day after initial dosing) 5, or 12. At each time point, histopathological examination of the kidney and immunohistochemistry for biomarkers, kidney injury molecule-1 (Kim-1), lipocalin (NGAL), clusterin (CLU), cystatin C (CysC) and β2-microglobulin (β2M) were performed. Biomarker levels were measured in urine and blood. In both treatment groups, degenerated/necrotic proximal tubules and regenerated tubules were mainly observed on days 5 and 12, respectively. At the same time as these tubular injuries, urinary Kim-1, CysC and β2M levels were increased. Moreover, urinary levels of CysC and β2M in GM-treated animals and Kim-1 in CDDP-treated animals increased (on day 2) prior to tubular injury on day 5. This was considered to reflect the characteristics of drug toxicity. Although almost all of the biomarkers in blood were not sufficiently sensitive to detect proximal tubular injury, urinary and plasma β2M levels simultaneously increased. Therefore, in addition to urinary Kim-1, CysC and β2M levels, plasma β2M levels were also considered useful for detecting proximal tubular injury.
authors.affiliation: Safety Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation, 1-1-1 Kazusakamatari, Kisarazu, Chiba 292-0818, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kuwata
authors.affiliation: Safety Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Itsuko
authors.initials: I
authors.lastname: Nakamura
authors.affiliation: Research Strategy & Planning Department, Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Ide
authors.affiliation: Safety Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation, 1-1-1 Kazusakamatari, Kisarazu, Chiba 292-0818, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Sato
authors.affiliation: Safety Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation, 1-1-1 Kazusakamatari, Kisarazu, Chiba 292-0818, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Nishikawa
authors.affiliation: Safety Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation, 1-1-1 Kazusakamatari, Kisarazu, Chiba 292-0818, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Tanaka
keywords: biomarker; cisplatin; gentamicin; immunohistochemistry; kidney; proximal tubular injury