Lack of the growth factor midkine enhances survival against cisplatin-induced renal damage.
Although cisplatin acts directly on proximal tubule epithelial cells and causes cell death, little is known regarding the biological significance of its secondary effects, such as inflammation. The growth factor midkine is highly expressed in the proximal tubule and exerts ambivalent activities as to cisplatin nephrotoxicity, ie, anti-apoptotic and chemotactic ones. Here we report that midkine-deficient mice show a significantly higher survival rate than wild-type mice. The levels of blood urea nitrogen and tubular degeneration and apoptosis were higher in wild-type mice despite the anti-apoptotic activity of midkine. We found that recruitment of neutrophils was more enhanced in wild-type mice, this being consistent with the chemotactic activity of midkine. Midkine expression in wild-type mice persisted for 24 hours, and then dramatically decreased. Preadministration of midkine anti-sense oligodeoxyribonucleotide to wild-type mice suppressed midkine expression, and consequently neutrophil infiltration. It is of note that neutrophil infiltration, apoptosis, and elevation of blood urea nitrogen became conspicuous sequentially, namely 1, 2, and 3 days after cisplatin administration, respectively. These findings suggest that early molecular events involving midkine induce inflammatory response and their circuits eventually enhance the death of the proximal tubule epithelial cells. The results indicate the crucial role of inflammation in cisplatin-induced renal damage, and provide a candidate molecular target for its prevention.
Kawai
Hanayo
H
Department of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Sato
Waichi
W
Yuzawa
Yukio
Y
Kosugi
Tomoki
T
Matsuo
Seiichi
S
Takei
Yoshifumi
Y
Kadomatsu
Kenji
K
Muramatsu
Takashi
T
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001806:Blood Urea Nitrogen; D015152:Blotting, Northern; D015153:Blotting, Western; D002470:Cell Survival; D002945:Cisplatin / Q000009:adverse effects*; D016207:Cytokines / Q000235:genetics* / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D020287:In Situ Nick-End Labeling; D007249:Inflammation; D007668:Kidney / Q000187:drug effects / Q000293:injuries / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D000078792:Midkine; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000494:pharmacology; D012260:Ribonucleases / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D016207:Cytokines; D016376:Oligonucleotides, Antisense; D000078792:Midkine; D012260:Ribonucleases; D002945:Cisplatin