| 摘要: | Background. Gentamicin, a widely used antibiotic for the
treatment of bacterial infection, can cause nephrotoxicity.
Tetramethylpyrazine (TMP) is a compound purified
from the rhizome of Ligusticum wallichi (called chuanxiong
in Chinese). Besides its protection against ischaemia–
reperfusion injury and nephritis in mice, we previously
reported that TMP reverses gentamicin-induced apoptosis
in rat kidneys. Haem oxygenase-1 (HO-1) induction
by TMP has also been shown to attenuate myocardial ischaemia/
reperfusion injury in rats.
Methods.We used rat renal tubular (NRK-52E) cells, transformed
cells with HO-1 overexpression or knockdown, and
an adenovirus carrying the HO-1 gene (Adv-HO-1) as gene
therapy targeting murine kidneys to explore the role of HO-
1 in protection by TMP against gentamicin-induced toxicity
both in vitro and in vivo. We evaluated the protective
effects of HO-1 on several apoptotic parameters induced
by gentamicin: cleaved caspases-3 and -9, cycloxygenase-2
(Cox-2) and subcellular localization of nuclear factor kappa
B-p65 (NF-κB-p65), Bcl-xl and HS-1-associated protein
(Hax-1) in NRK-52E cells.
Results. NRK-52E cells treated with TMP exhibited transcriptional
upregulation of the HO-1 protein by approximately
twofold. Overexpression of HO-1 in NRK-52E cells
significantly increased mitochondrial protein levels of the
antiapoptotic molecules, Bcl-xL and Hax-1, and markedly
decreased the NADPH oxidase activity and proinflammatory
molecules, NF-κB-p65 and Cox-2, which might decrease
gentamicin-induced activation of caspases-9 and -3.
Conversely, NRK-52E cells with HO-1 knockdown significantly
exacerbated gentamicin-induced tubular cell apoptosis.
Additionally, the concomitant HO-1 induction by TMP
Correspondence and offprint requests to: Shu-Hui Juan, Department
of Physiology, Graduate Institute of Medical Sciences and
Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan.
Tel: +886-2-27361661; Ext. 3178; Fax: +886-2-23461737; E-mail:
[email protected]
was also evident in vivo, and HO-1 therapy markedly attenuated
gentamicin-induced renal apoptosis to a similar
extent as TMP pretreatment.
Conclusions. Collectively, we suggest that HO-1 induced
by TMP might, at least in part, protect against gentamicininduced
nephrotoxicity through antiapoptotic and antiinflammatory
mechanisms, and that it may have therapeutic
potential for patientswith renal disease. This is also the first
demonstration that HO-1 increases Hax-1 mitochondrial localization.
Keywords: apoptosis; haem oxygenase; HS-1-associated
protein (HAX-1); NADPH oxidase; tetramethylpyrazine
(TMP) |
