title: One dose of cyclosporine A is protective at initiation of folic acid-induced acute kidney injury in mice.
abstract: BACKGROUND
  In most patients, acute kidney injury (AKI) represents the combined effects of ischemic, toxic and inflammatory insults. No effective pharmacologic interventions have been developed to prevent AKI or to improve outcomes to date. Cyclosporine A (CsA) is a calcineurin inhibitor that mediates T-cell receptor signaling, suppresses inflammatory cytokine expression and inhibits leukocyte migration. It is also a potent inhibitor of mitochondrial permeability, protecting cells from death. These properties make it a potentially valuable drug to prevent or treat AKI. It does, however, carry a significant risk of nephrotoxicity, especially with chronic use. By contrast, a single dose of CsA may be protective while limiting the risk of nephrotoxicity.
  
  
  METHODS
  We conducted a controlled animal experiment in male CD-1 mice. Specifically, mice were subjected to folic acid (FA)-induced AKI and then randomly assigned to sham operation or one of three dosage of CsA treatment groups. Results Intraperitoneal injection of FA consistently induced AKI. Serum interleukin (IL)-6 and urinary neutrophil gelatinase-associated lipocalin (NGAL) rose 1 day after FA injection. Compared to sham treatment, one dose (1 and 5 mg/kg body weight) of CsA significantly reduced kidney tubular cell apoptosis, serum creatinine, blood urea, serum IL-6 and urinary NGAL 2 days after FA injection. It was also shown to block the inflammatory mediator tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) expression, nuclear factor kappa-B (NFκB) activation, inflammatory cell infiltration and interstitial fibrosis 14 days after treatment in a dose-dependent fashion. By contrast, a dose of 10 mg/kg body weight CsA resulted in nephrotoxicity in the setting of FA-induced AKI.
  
  
  CONCLUSIONS
  A single dose of CsA, currently used for organ transplant, significantly protects mice from FA-induced AKI, presumably through inhibition of cell death, inflammatory reaction, interstitial cell infiltration and fibrosis. The protective effects have the potential to open a completely new line of investigation in the prevention and treatment of AKI.
authors.affiliation: The Clinical Research, Investigation and Systems Modeling of Acute illness Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wen
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Peng
authors.forename: Yingjian
authors.initials: Y
authors.lastname: Li
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Wang
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Bishop
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Chedwick
authors.forename: Kai
authors.initials: K
authors.lastname: Singbartl
authors.forename: John A
authors.initials: JA
authors.lastname: Kellum
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000209:Acute-Phase Proteins / Q000652:urine; D000818:Animals; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000008:administration & dosage* / Q000633:toxicity; D000074049:Cytokine TWEAK; D004195:Disease Models, Animal; D005355:Fibrosis; D005492:Folic Acid / Q000633:toxicity*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000633:toxicity; D015850:Interleukin-6 / Q000097:blood; D000071068:Lipocalin-2; D054834:Lipocalins / Q000652:urine; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D015513:Oncogene Proteins / Q000652:urine; D048069:Tumor Necrosis Factors / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; D000074049:Cytokine TWEAK; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D000071068:Lipocalin-2; D054834:Lipocalins; D016328:NF-kappa B; D015513:Oncogene Proteins; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors; C071332:Lcn2 protein, mouse; D016572:Cyclosporine; D005492:Folic Acid; D003404:Creatinine