Enhancement of chronic cyclosporine nephrotoxicity by sodium depletion in an experimental mouse model

Takeshi F. Andoh, Tri T. Lam, Jessie Lindsley, Charles E. Alpers, William M. Bennett

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

The major adverse reaction to cyclosporine A (CsA) is chronic nephrotoxicity. To elucidate the pathogenesis of CsA nephrotoxicity and the potential role of the renin-angiotensin system (RAS) in mediating this toxicity, a reliable mouse model would enable us to take advantage of various probes, and gene knockout animals available in this species, but not in the rat, would be extremely useful. Using the manoeuvre of sodium depletion and activation of RAS, an experimental model in the mouse has been developed to reproduce structural and functional characteristics of chronic CsA nephrotoxicity in humans. Mice were treated with CsA subcutaneously at dosages of 10 mg/kg per day and 30 mg/kg per day or olive oil as a placebo on a low sodium diet (LS) (0.01% sodium) for 28 days. Comparisons were made with mice treated with CsA at 100 mg/kg per day on a normal sodium diet (NS 0.4% sodium) for 56 days. Cyclosporine A treatment induced significant increases in serum creatinine and blood urea nitrogen (BUN) and a decrease in creatinine clearance in mice on LS (P<0.05 vs placebo). Sodium-depleted animals on CsA 30 mg/kg per day treatment developed significant histological lesions in the kidneys consisting of tubulomterstitial fibrosis, arteriolopathy, nephrocalcinosis, and tubular injury after 28 days (P<0.001 vs placebo). By contrast, CSA treatment in mice on NS did not induce functional and structural abnormalities in the kidneys even up to 56 days at a higher dose. This mouse model can be useful to gain further into the pathogenetic mechanisms of chronic CsA nephropathy.

Original languageEnglish (US)
Pages (from-to)471-478
Number of pages8
JournalNephrology
Volume3
Issue number6
DOIs
StatePublished - 1997

Keywords

  • Arteriolopathy
  • Cyclosporine
  • Knockout mouse
  • Mice
  • Nephrotoxicity
  • Renin- angiotensin system tubulointerstitial fibrosis

ASJC Scopus subject areas

  • Nephrology

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