Urinary biomarkers in hexachloro‐1:3‐butadiene‐induced acute kidney injury in the female Hanover Wistar rat; correlation of α‐glutathione S‐transferase, albumin and kidney injury molecule‐1 with histopathology and gene expression

Abstract

Hexachloro-1:3-butadiene (HCBD) causes kidney injury specific to the pars recta of the proximal tubule. In the present studies, injury to the nephron was characterized at 24 h following a single dose of HCBD, using a range of quantitative urinary measurements, renal histopathology and gene expression. Multiplexed renal biomarker measurements were performed using both the Meso Scale Discovery (MSD) and Rules Based Medicine platforms. In a second study, rats were treated with a single nephrotoxic dose of HCBD and the time course release of a range of traditional and newer urinary biomarkers was followed over a 25 day period. Urinary albumin (a marker of both proximal tubular function and glomerular integrity) and α-glutathione S-transferase (α-GST, a proximal tubular cell marker of cytoplasmic leakage) showed the largest fold change at 24 h (day 1) after dosing. Most other markers measured on either the MSD or RBM platforms peaked on day 1 or 2 post-dosing, whereas levels of kidney injury molecule-1 (KIM-1), a marker of tubular regeneration, peaked on day 3/4. Therefore, in rat proximal tubular nephrotoxicity, the measurement of urinary albumin, α-GST and KIM-1 is recommended as they potentially provide useful information about the function, degree of damage and repair of the proximal tubule. Gene expression data provided useful confirmatory information regarding exposure of the kidney and liver to HCBD, and the response of these tissues to HCBD in terms of metabolism, oxidative stress, inflammation, and regeneration and repair.

Wound Fluid Diagnostics in Diabetic Foot Ulcers

“…The analysis of a complete set of mediators can therefore be considered to be of more value than the single analysis of only one single analyte (Gardy et al 2009;de Jager et al 2003). Although protein microarray technology has been successfully applied for the analysis of multiple analytes in complex biological mixtures -such as plasma, serum, urine and cerebrospinal fluid-publications using protein arrays for the analysis of wound status are rare (Hsu et al 2008;Weigelt et al 2009;Craig-Schapiro et al 2011;Swain et al 2011). For instance, Grimstad et al measured the concentration of 27 different cytokines in wound fluid derived from acute wounds using a bead-based system (Grimstad et al 2011).…”

Correlation of Histopathology, Urinary Biomarkers, and Gene Expression Responses Following Hexachloro-1:3-Butadiene–induced Acute Nephrotoxicity in Male Hanover Wistar Rats

“…Significance was set at three levels: *p < .05, **p < .01, and ***p < .001. Where used, the ''fold increase'' or ''fold decrease'' in a parameter is the ratio of the mean value of the HCBD-treated group in relation to the mean value of the concurrent control group (Swain et al 2011(Swain et al , 2012.…”

“…At 10.00 hr, 6 animals from each treatment group (rat numbers 1 to 6) were weighed and treated with corn oil (vehicle-treated controls); the remaining 6 animals (rat numbers 7 to 12) were weighed and treated with HCBD at 45 mg/kg. The administered dose of HCBD was chosen based on the work from preliminary studies (Swain et al 2011(Swain et al , 2012, in which 45 mg/kg of HCBD produced consistent and acute evidence of histopathologic proximal tubular degeneration. After treatment, rats were replaced in their communal cages, with diet and water ad libitum.…”

“…Indeed, one limitation identified in the initial renal biomarker qualification submission process concerned the need for recovery studies to demonstrate that reversibility of histopathologic renal lesions could be similarly monitored by biomarker changes . Following on from the preliminary dose-response and time course studies (Swain et al 2011), and the dose-response investigations (Swain et al 2012), the aim of the present work was to characterize the temporal responses in several traditionally used and more recently proposed urinary biomarkers, employing HCBD-induced proximal tubule damage and to correlate the patterns of change in urinary biomarker levels with tubular histopathology and gene expression.…”

Testes sanguíneos de biomarcadores para diagnóstico e tratamento de desordens mentais: foco em esquizofrenia

“…A Rat KidneyMAP TM has now been developed as a multiplexed immunoassay by Rules Based Medicine in collaboration with the PSTC for early detection of renal damage, which is common in drug development programs (http://www. rulesbasedmedicine.com/products-services/rodentmap-services/ rat-kidneymap/) 64 .…”