Department of Pediatrics, University of Pittsburgh School of Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania.
Buck Institute for Research on Aging, Novato, California.
J Am Soc Nephrol. 2024 Feb 1;35(2):135-148. doi: 10.1681/ASN.0000000000000266. Epub 2023 Dec 4.
In this study, we demonstrate that a common, low-cost compound known as octanedioic acid (DC 8 ) can protect mice from kidney damage typically caused by ischemia-reperfusion injury or the chemotherapy drug cisplatin. This compound seems to enhance peroxisomal activity, which is responsible for breaking down fats, without adversely affecting mitochondrial function. DC 8 is not only affordable and easy to administer but also effective. These encouraging findings suggest that DC 8 could potentially be used to assist patients who are at risk of experiencing this type of kidney damage.
Proximal tubules are rich in peroxisomes, which are damaged during AKI. Previous studies demonstrated that increasing peroxisomal fatty acid oxidation (FAO) is renoprotective, but no therapy has emerged to leverage this mechanism.
Mice were fed with either a control diet or a diet enriched with dicarboxylic acids, which are peroxisome-specific FAO substrates, then subjected to either ischemia-reperfusion injury-AKI or cisplatin-AKI models. Biochemical, histologic, genetic, and proteomic analyses were performed.
Both octanedioic acid (DC 8 ) and dodecanedioic acid (DC 12 ) prevented the rise of AKI markers in mice that were exposed to renal injury. Proteomics analysis demonstrated that DC 8 preserved the peroxisomal and mitochondrial proteomes while inducing extensive remodeling of the lysine succinylome. This latter finding indicates that DC 8 is chain shortened to the anaplerotic substrate succinate and that peroxisomal FAO was increased by DC 8 .
DC 8 supplementation protects kidney mitochondria and peroxisomes and increases peroxisomal FAO, thereby protecting against AKI.
在这项研究中，我们证明了一种常见的、低成本的化合物，即辛二酸（DC8），可以保护小鼠免受缺血再灌注损伤或化疗药物顺铂引起的肾脏损伤。这种化合物似乎增强了过氧化物酶体的活性，而过氧化物酶体负责分解脂肪，而不会对线粒体功能产生不利影响。DC8 不仅价格实惠且易于给药，而且还具有疗效。这些令人鼓舞的发现表明，DC8 可能有潜力被用于帮助那些有发生这种类型的肾脏损伤风险的患者。
近端肾小管富含过氧化物酶体，而过氧化物酶体在急性肾损伤（AKI）中受到损伤。先前的研究表明，增加过氧化物酶体脂肪酸氧化（FAO）具有肾脏保护作用，但尚未出现利用这种机制的疗法。
用含有二羧酸的饮食喂养小鼠，二羧酸是过氧化物酶体特异性 FAO 底物，然后使小鼠暴露于缺血再灌注损伤-AKI 或顺铂-AKI 模型中。进行了生化、组织学、遗传和蛋白质组学分析。
辛二酸（DC8）和十二烷二酸（DC12）均可预防暴露于肾损伤的小鼠中 AKI 标志物的升高。蛋白质组学分析表明，DC8 保留了过氧化物酶体和线粒体蛋白质组，同时诱导了赖氨酸琥珀酰化组的广泛重塑。这一发现表明，DC8 被链缩短为补料基质琥珀酸，并且 DC8 增加了过氧化物酶体的 FAO。
DC8 补充剂可保护肾脏线粒体和过氧化物酶体，并增加过氧化物酶体的 FAO，从而预防 AKI。
