Deletion of the kinase domain in death-associated protein kinase attenuates tubular cell apoptosis in renal ischemia-reperfusion injury

Masanori Kishino, Kazunori Yukawa, Katsuaki Hoshino, Akihiko Kimura, Nobuyuki Shirasawa, Haruhisa Otani, Tetsuji Tanaka, Kyoko Owada-Makabe, Yuji Tsubota, Masanobu Maeda, Masakazu Ichinose, Kiyoshi Takeda, Shizuo Akira, Masatoshi Mune

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

Abstract

Death-associated protein kinase (DAPK) is a calcium/calmodulin-dependent serine/threonine kinase localized to renal tubular epithelial cells. To elucidate the contribution of DAPK activity to apoptosis in renal ischemia-reperfusion (IR) injury, wild-type (WT) mice and DAPK-mutant mice, which express a DAPK deletion mutant that lacks a portion of the kinase domain, were subjected to renal pedicle clamping and reperfusion. After IR, DAPK activity was elevated in WT kidneys but not in mutant kidneys (1785.7 ± 54.1 pmol/ min/mg versus 160.7 ± 60.6 pmol/min/mg). Furthermore, there were more TUNEL-positive nuclei and activated caspase 3-positive cells in WT kidneys than in mutant kidneys after IR (24.0 ± 5.9 nuclei or 9.4 ± 0.6 cells per high-power field [HPF] versus 6.3 ± 2.2 nuclei or 4.4 ± 0.7 cells/HPF at 40 h after ischemia). In addition, the increase in p53-positive tubule cells after IR was greater in WT kidney than in mutant kidneys (9.9 ± 1.4 cells/HPF versus 0.8 ± 0.4 cells/HPF), which is consistent with the theory that DAPK activity stabilizes p53 protein. Finally, serum creatinine levels after IR were higher in WT mice than in mutant mice (2.54 ± 0.34 mg/dl versus 0.87 ± 0.24 mg/dl at 40 h after ischemia). Thus, these results indicate that deletion of the kinase domain from DAPK molecule can attenuate tubular cell apoptosis and renal dysfunction after IR injury.

Original languageEnglish
Pages (from-to)1826-1834
Number of pages9
JournalJournal of the American Society of Nephrology
Volume15
Issue number7
DOIs
Publication statusPublished - 2004 Jul

ASJC Scopus subject areas

  • Nephrology

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