Blocking tumor necrosis factor-alpha inhibits folic acid-induced acute renal failure.
Systemic administration of mice with folic acid (FA) has been used for studying the pathogenesis of acute renal failure. However, the molecular mechanisms by which FA induces acute renal failure remain poorly understood. We found that CD-1 mice treated with FA developed acute renal failure characterized by increased blood urea nitrogen, necrosis, and apoptosis of tubular epithelial cells. Compared to control mice, tumor necrosis factor-alpha (TNF-alpha) was markedly elevated in blood and kidneys of these FA-treated mice, accompanied by markedly reduced expression of anti-apoptotic protein BclxL in their kidneys. In vivo administration of FA-treated CD-1 mice with neutralizing anti-TNF-alpha antibody restored the expression of BclxL in kidneys and inhibited the necrosis and apoptosis of renal tubular epithelial cells, leading to the amelioration of acute renal failure. In ex vivo cultures, we found that FA enhanced production of TNF-alpha, decreased expression of BclxL protein, and induced apoptosis of mouse cortical tubule (MCT) cells. Addition of neutralizing anti-TNF-alpha antibody, but not control IgG, in the cultures markedly blocked the apoptotic death of FA-treated MCT cells and restored expression of BclxL to the same levels as those MCT cells cultured in the absence of FA. All these results suggest that TNF-alpha is a critical inflammatory cytokine responsible for FA-mediated acute renal failure. Furthermore, in vivo administration of anti-TNF-alpha antibody may be proved as an effective approach for acute renal failure prevention and treatment.
Wan
Bing
B
Joint Immunology Laboratory of Institute of Health Sciences, Chinese Academy of Sciences and Medical College of Shanghai, Jiao Tong University, Shanghai, China.
Hao
Li
L
Qiu
Yuhua
Y
Sun
Zhongwen
Z
Cao
Qi
Q
Zhang
Yi
Y
Zhu
Tongyu
T
Wang
Hao
H
Zhang
Yanyun
Y
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000503:physiopathology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001806:Blood Urea Nitrogen; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D005492:Folic Acid / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D009336:Necrosis / Q000473:pathology; D009500:Neutralization Tests; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000097:blood; D051020:bcl-X Protein / Q000378:metabolism
D000906:Antibodies; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D005492:Folic Acid