Identification of novel indicators of cyclosporine A nephrotoxicity in a CD-1 mouse model

Journal Article · Fri Apr 15 04:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.02.015· OSTI ID:21535277

O'Connell, Sein; Slattery, Craig; Ryan, Michael P; McMorrow, Tara

The calcineurin inhibitor cyclosporine A (CsA) is a widely used immunosuppressive agent. However, nephrotoxicity is a serious side effect observed in patients which limits clinical use of CsA. CsA nephrotoxicity is associated with tubulointerstitial injury progressing to nephropathy. This is typically diagnosed by invasive renal biopsy and is often only detected when the disease process is well advanced. Therefore identification of novel, early indicators of CsA nephrotoxicity could be clinically advantageous. This study aimed to establish a murine model of CsA nephrotoxicity and to identify urinary proteins that may indicate the onset of CsA-induced nephropathy using 2-D gel electrophoresis. CsA nephrotoxicity was induced in CD-1 mice by daily CsA administration for 4 weeks. By week 4, elevated serum creatinine and proteinuria were observed after CsA treatment indicating significant renal dysfunction. Decreased cadherin-1, increased {alpha}-smooth muscle actin and fibroblast specific protein 1 in kidney tissue indicated disruption of normal tubular architecture. Alterations in podocin and uromodulin were also observed which may indicate damage to other segments of the nephron. Proteomic analysis of urine identified a number of differentially regulated proteins that may be involved in early CsA nephropathy including cadherin 1, superoxide dismutase and vinculin. These findings suggest novel mechanisms of CsA nephrotoxicity and identify novel potential markers of the disease.

• OSTI ID: 21535277
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 252; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACTIN
ANIMAL TISSUES
ANIMALS
BODY
CONNECTIVE TISSUE
CYCLOSPORINE
DAMAGE
DRUGS
ELECTROPHORESIS
ENZYMES
GROWTH FACTORS
IMMUNOSUPPRESSIVE DRUGS
KIDNEYS
MAMMALS
MICE
MITOGENS
MUSCLES
ORGANIC COMPOUNDS
ORGANS
OXIDOREDUCTASES
PATIENTS
PEPTIDES
PROTEINS
RODENTS
SUPEROXIDE DISMUTASE
VERTEBRATES