Renal liver-type fatty acid binding protein (L-FABP) attenuates acute kidney injury in aristolochic acid nephrotoxicity

Am J Pathol. 2011 Mar;178(3):1021-32. doi: 10.1016/j.ajpath.2010.12.002.

Abstract

Injection of aristolochic acid (AA) in mice causes AA-induced nephrotoxicity, in which oxidative stress contributes to development of tubulointerstitial damage (TID). Liver-type fatty acid binding protein (L-FABP) is expressed in human proximal tubules and has an endogenous antioxidative function. The renoprotection of renal L-FABP was examined in a model of AA-induced nephrotoxicity. Established human L-FABP (hL-FABP) transgenic (Tg) mice and wild-type (WT) mice were treated with AA for up to 5 days. Mice were sacrificed on days 1, 3, and 5 after the start of AA injection. Although mouse L-FABP was not expressed in proximal tubules of WT mice, hL-FABP was expressed in proximal tubules of Tg mice. The expression of renal hL-FABP was significantly increased in Tg mice administered AA (Tg-AA), compared with the control (saline-treated Tg mice). In WT-AA mice, there was high urinary excretion of N(ε)-(hexanoyl)-lysine, the production of heme oxygenase-1 and receptor for advanced glycation end products increased, and TID was provoked. In contrast, renal hL-FABP in Tg-AA mice suppressed production of N(ε)-(hexanoyl)lysine, heme oxygenase-1, and receptor for advanced glycation end products. Renal dysfunction was significantly milder in Tg-AA mice than in WT-AA mice. The degree of TID was significantly attenuated in Tg-AA mice, compared with WT-AA. In conclusion, renal hL-FABP reduced the oxidative stress in AA-induced nephrotoxicity and attenuated TID.

MeSH terms

  • Acute Kidney Injury / chemically induced
  • Acute Kidney Injury / metabolism
  • Acute Kidney Injury / pathology*
  • Animals
  • Aquaporin 1 / metabolism
  • Aristolochic Acids
  • Body Weight
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Fatty Acid-Binding Proteins / blood
  • Fatty Acid-Binding Proteins / metabolism*
  • Fatty Acid-Binding Proteins / urine
  • Gene Expression Regulation
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Immunohistochemistry
  • Kidney / metabolism*
  • Kidney / pathology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Oxidative Stress
  • Procollagen / genetics
  • Procollagen / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism

Substances

  • Aristolochic Acids
  • Chemokine CCL2
  • FABP1 protein, human
  • Fatty Acid-Binding Proteins
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Procollagen
  • Transforming Growth Factor beta
  • Aquaporin 1
  • aristolochic acid I