Journal Article

Antioxidation and anti-inflammation by haem oxygenase-1 contribute to protection by tetramethylpyrazine against gentamicin-induced apoptosis in murine renal tubular cells

Yuh-Mou Sue, Ching-Feng Cheng, Chih-Cheng Chang, Ying Chou, Cheng-Hsien Chen and Shu-Hui Juan

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 24, issue 3, pages 769-777
Published in print March 2009 | ISSN: 0931-0509
Published online October 2008 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfn545
Antioxidation and anti-inflammation by haem oxygenase-1 contribute to protection by tetramethylpyrazine against gentamicin-induced apoptosis in murine renal tubular cells

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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 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 gentamicin-induced nephrotoxicity through antiapoptotic and anti-inflammatory mechanisms, and that it may have therapeutic potential for patients with 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)

Journal Article.  5651 words.  Illustrated.

Subjects: Nephrology

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