Identification of putative gene based markers of renal toxicity.

Abstract

This study, designed and conducted as part of the International Life Sciences Institute working group on the Application of Genomics and Proteomics, examined the changes in the expression profile of genes associated with the administration of three different nephrotoxicants--cisplatin, gentamicin, and puromycin--to assess the usefulness of microarrays in the understanding of mechanism(s) of nephrotoxicity. Male Sprague-Dawley rats were treated with daily doses of puromycin (5-20 mg/kg/day for 21 days), gentamicin (2-240 mg/kg/day for 7 days), or a single dose of cisplatin (0.1-5 mg/kg). Groups of rats were sacrificed at various times after administration of these compounds for standard clinical chemistry, urine analysis, and histological evaluation of the kidney. RNA was extracted from the kidney for microarray analysis. Principal component analysis and gene expression-based clustering of compound effects confirmed sample separation based on dose, time, and degree of renal toxicity. In addition, analysis of the profile components revealed some novel changes in the expression of genes that appeared to be associated with injury in specific portions of the nephron and reflected the mechanism of action of these various nephrotoxicants. For example, although puromycin is thought to specifically promote injury of the podocytes in the glomerulus, the changes in gene expression after chronic exposure of this compound suggested a pattern similar to the known proximal tubular nephrotoxicants cisplatin and gentamicin; this prediction was confirmed histologically. We conclude that renal gene expression profiling coupled with analysis of classical end points affords promising opportunities to reveal potential new mechanistic markers of renal toxicity.

Identification of genes involved in gentamicin-induced nephrotoxicity in rats – A toxicogenomic investigation

“…The down-regulation of KLK1 (Kallikrein 1) after gentamicin administration was previously described by Amin et al (2004). In addition gentamicin-treated rats were shown to have strongly reduced levels of urinary Kallikrein (Higa et al, 1985).…”

Normal Ranges and Variability of Novel Urinary Renal Biomarkers in Sprague-Dawley Rats

“…The determination to characterize better biomarkers has been given additional impetus by the discovery of a number of potential novel biomarkers through the use of transcriptomic technologies (e.g., Amin et al 2004;Thukral et al 2005). This has enhanced the prospect of making available a range of sensitive and specific biomarkers that will have superior diagnostic utility.…”

Effects of Mercuric Chloride on Gene Expression in NRK-52E Cells

“…Renal toxicity commonly occurs after administration of xenobiotics, including heavy metals. The process is typically started by a toxic injury to tubular epithelial cells in various nephron segments or by injury to specific cell types in the glomerulus (Amin et al, 2004). Mercuric chloride produces toxic effects on the third segment (S3) of the proximal tubule of kidney (Carranza-Rosales et al, 2005).…”

“…This is accompanied by alterations in the expression of other genes (e.g. KIM1, cystatin C, clusterin and osteopontin) that contribute either to cellular repair or recovery of renal function (Amin et al, 2004). A number of approaches have been used to identify components of the complex responses to nephrotoxicants, which are not only potential biomarkers but also therapeutic targets.…”

“…A number of approaches have been used to identify components of the complex responses to nephrotoxicants, which are not only potential biomarkers but also therapeutic targets. Gene expression in acute renal failure has been analyzed with microarrays in several studies (Amin et al, 2004;Huang et al, 2001;Safirstein, 2004). However, the results vary because of a lot of potential confounding factor, such as species difference, injury difference, microarray platform difference and dose and time difference.…”