Midkine antisense oligodeoxyribonucleotide inhibits renal damage induced by ischemic reperfusion.
BACKGROUND
Midkine, a heparin-binding growth factor, is involved in the migration of inflammatory cells. The inflammatory cell migration to the tubulointerstitium of the kidney after ischemia/reperfusion (I/R) injury is attenuated in midkine gene-deficient mice, resulting in better preservation of the tubulointerstitium compared with wild-type mice. In the present investigation, we planned to evaluate the usefulness of antisense midkine for the therapy of ischemic renal failure.


METHODS
Midkine antisense phosphorothioate oligodeoxyribonucleotide (ODN) at a dose of 1 mg/kg in saline was intravenously administered to mice 1 day before or after I/R. The kidneys were removed for examination 1, 2, 3, and 7 days after I/R.


RESULTS
It was rapidly incorporated into proximal tubular epithelial cells, and inhibited midkine synthesis, leading to reduced migration of inflammatory cells to the injured epithelial layer. Consequently, the midkine antisense ODN-treated animals exhibited less severe renal damage than untreated or midkine sense ODN-treated animals 2 days after I/R as assessed by morphologic criteria and blood urea nitrogen (BUN) and serum creatinine levels. Midkine expression, BUN, and serum creatinine levels were not significantly different between injection of midkine antisense ODN before and after ischemic injury.


CONCLUSIONS
These results indicate that intravenous injection of midkine antisense ODN is a candidate for a novel therapeutic strategy against acute tubulointerstitial injury induced by I/R injury.
Sato
Waichi
W
Department of Clinical Immunology of Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Takei
Yoshifumi
Y
Yuzawa
Yukio
Y
Matsuo
Seiichi
S
Kadomatsu
Kenji
K
Muramatsu
Takashi
T
D000818:Animals; D001483:Base Sequence; D001806:Blood Urea Nitrogen; D045744:Cell Line, Tumor; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000235:genetics*; D007511:Ischemia; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000078792:Midkine; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D012004:Rectal Neoplasms; D012079:Renal Circulation / Q000187:drug effects; D015427:Reperfusion Injury / Q000517:prevention & control*; D013873:Thionucleotides / Q000494:pharmacology
D016207:Cytokines; D020319:Oligodeoxyribonucleotides, Antisense; D013873:Thionucleotides; D000078792:Midkine; D003404:Creatinine