title: Evaluation of cystatin C as an early biomarker of cadmium nephrotoxicity in the rat.
abstract: Cadmium (Cd) is a nephrotoxic environmental pollutant that causes insidious injury to the proximal tubule that results in severe polyuria and proteinuria. Cystatin C is a low molecular weight protein that is being evaluated as a serum and urinary biomarker for various types of ischemic and nephrotoxic renal injury. The objective of the present study was to determine if cystatin C might be a useful early biomarker of Cd nephrotoxicity. Male Sprague-Dawley rats were given daily injections of Cd for up to 12 weeks. At 3, 6, 9 and 12 weeks, urine samples were analyzed for cystatin C, protein, creatinine, β2 microglobulin and kidney injury molecule-1. The results showed that Cd caused a significant increase in the urinary excretion of cystatin C that occurred 3-4 weeks before the onset of polyuria and proteinuria. Serum levels of cystatin C were not altered by Cd. Immunolabeling studies showed that Cd caused the relocalization of cystatin C from the cytoplasm to the apical surface of the epithelial cells of the proximal tubule. The Cd-induced changes in cystatin C labelling paralleled those of the brush border transport protein, megalin, which has been implicated as a mediator of cystatin C uptake in the proximal tubule. These results indicate that Cd increases the urinary excretion of cystatin C, and they suggest that this effect may involve disruption of megalin-mediated uptake of cystatin C by epithelial cells of the proximal tubule.
authors.affiliation: Department of Pharmacology, Midwestern University, 555 31st Street, Downers Grove, IL, 60515, USA. wprozi@midwestern.edu.
authors.forename: Walter C
authors.initials: WC
authors.lastname: Prozialeck
authors.affiliation: Department of Pharmacology, Midwestern University, 555 31st Street, Downers Grove, IL, 60515, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: VanDreel
authors.affiliation: Department of Pharmacology, Midwestern University, 555 31st Street, Downers Grove, IL, 60515, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Ackerman
authors.affiliation: Department of Pharmacology, Midwestern University, 555 31st Street, Downers Grove, IL, 60515, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Stock
authors.affiliation: Department of Pharmacology, Midwestern University, 555 31st Street, Downers Grove, IL, 60515, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Papaeliou
authors.affiliation: Department of Pharmacology, Midwestern University, 555 31st Street, Downers Grove, IL, 60515, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Yasmine
authors.affiliation: Department of Pharmacology, Midwestern University, 555 31st Street, Downers Grove, IL, 60515, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Wilson
authors.affiliation: Department of Pharmacology, Midwestern University, 555 31st Street, Downers Grove, IL, 60515, USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Lamar
authors.affiliation: Department of Pharmacology, Midwestern University, 555 31st Street, Downers Grove, IL, 60515, USA.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Sears
authors.affiliation: Department of Biomedical Sciences, Midwestern University, 555 31st Street, Downers Grove, IL, 60515, USA.
authors.forename: Joshua Z
authors.initials: JZ
authors.lastname: Gasiorowski
authors.affiliation: Department of Physiology, Midwestern University, 555 31st Street, Downers Grove, IL, 60515, USA.
authors.forename: Karyn M
authors.initials: KM
authors.lastname: DiNovo
authors.affiliation: Renal Division, Brigham and Woman's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Vishal S
authors.initials: VS
authors.lastname: Vaidya
authors.affiliation: Department of Pharmacology, Midwestern University, 555 31st Street, Downers Grove, IL, 60515, USA.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Edwards
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine*; D002104:Cadmium / Q000008:administration & dosage / Q000633:toxicity*; D015815:Cell Adhesion Molecules / Q000097:blood; D003404:Creatinine / Q000097:blood; D055316:Cystatin C / Q000097:blood / Q000652:urine*; D004785:Environmental Pollutants; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051381:Rats
chemical_list: D015415:Biomarkers; D002104:Cadmium; D015815:Cell Adhesion Molecules; D003404:Creatinine; D055316:Cystatin C; D004785:Environmental Pollutants; C110936:Havcr1 protein, rat
keywords: Biomarkers; Cadmium; Cystatin C; Nephrotoxicity; Proximal tubule