降低有毒醛類以達到治療小鼠急性腎損傷的效果

Reducing toxic aldehydes for treating acute kidney injury in mice

丁致中(Zhi-Zhong DING)

指導教授 ： 張以承

國立臺灣大學/醫學院/基因體暨蛋白體醫學研究所/碩士(2020年)

https://doi.org/10.6342/NTU202004018

摘要

日常生活中常存在有醛類的危害，這些有害醛類可能來自於酒精、二手菸、工業廢氣、食物腐壞等外在因子或者是經由體內代謝反應所產生。具高反應活性的醛類如4-hydroxynonenal（4-HNE）會與蛋白質產生共價鍵交互結合，進而影響正常蛋白質的構型並損害其功能。
在人體中，位於細胞粒線體內的乙醛脫氫酶(acetaldehyde dehydrogenase 2, ALDH2)主要負責將酒精的下游產物乙醛代謝為乙酸。除此之外，ALDH2同時也負責代謝其他有害的醛類如4-HNE。然而，在東亞地區有超過40％的人群帶有ALDH2基因的錯義性點突變(missense mutation, Glu487Lys)，使得這個酵素在異合子結構時活性失去60-80%，同合子結構時活性失去約90%，在後續的全基因組相關研究中也發現這個東亞人特有的點突變與腎功能有所關聯。
在我們的研究中，我們建立了缺血-再灌流的急性腎損傷小鼠模型，試圖用以探討ALDH2活化劑AD9308是否能應用於治療急性腎損傷。結果顯示，在小鼠體內產生急性腎損傷的前後施以ALDH2活化劑AD9308治療，可以有效改善腎功能並延長小鼠存活率，組織學檢查發現AD9308可以減少小鼠的腎小管損傷以及與4-HNE結合之蛋白堆積並避免腎組織的纖維化病變。
當前急性腎損傷的治療在臨床上以支持性治療為主，本研究開啟了藉由活化ALDH2以治療急性腎損傷的契機。

關鍵字

乙醛脫氫酶 ； 醛類 ； 急性腎損傷 ； 乙醛脫氫酶活化劑

並列摘要

In daily life, we are exposed to hazardous aldehydes. These harmful aldehydes may produce from exogenous factors such as alcohol beverage, cigarette smoking, factory exhaust, spoiled fruits or from endogenous intermediate metabolism. The highly active aldehydes such as 4-hydroxynonenal (4-HNE) form covalent binding with proteins, which change their structure resulting in protein dysfunction.
In human, acetaldehyde dehydrogenase 2 (ALDH2) enzymes that locate in cell mitochondria mainly metabolize acetaldehydes into acetic acid in alcohol metabolism pathway. Besides, ALDH2 also metabolizes a variety of toxic aldehydes including 4-HNE. However, approximate 40% of the East Asian population carry a single nucleotide polymorphism (SNP) of ALDH2 (rs671). The inactivating missense mutation is characteristic of the substitution of lysine for glutamate at position 487 (Glu487Lys) within the catalytic site of ALDH2. The ALDH2 enzymatic activity decreases by 60 to 80 % in heterozygotes (ALDH2*1) and 90 % in homozygotes (ALDH2*2). A large-scale meta-analysis of genome-wide association studies has reported that this polymorphism is significantly associated with renal function.
In this study, we established the mice acute kidney injury (AKI) model induces by ischemia-reperfusion-injury (IRI). ALDH2 activator AD9308 improved renal function and prolonged survival in AKI mice. Histological examination also showed that AD9308 reduced renal tubular damage, accumulation of 4-HNE-adducted proteins, and renal tissue fibrosis.
Present clinical treatments for AKI adopt supportive therapies. Our findings herald a new approach for treating AKI by activating ALDH2.

並列關鍵字

ALDH2 ； aldehydes ； 4-hydroxynonenal ； acute kidney injury ； ALDH2 activator

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