Dicarboxylic Acid Dietary Supplementation Protects against AKI

Significance StatementIn this study, we demonstrate that a common, low-cost compound known as octanedioic acid (DC8) 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. DC8 is not only affordable and easy to administer but also effective. These encouraging findings suggest that DC8 could potentially be used to assist patients who are at risk of experiencing this type of kidney damage.BackgroundProximal 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.MethodsMice 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.ResultsBoth octanedioic acid (DC8) and dodecanedioic acid (DC12) prevented the rise of AKI markers in mice that were exposed to renal injury. Proteomics analysis demonstrated that DC8 preserved the peroxisomal and mitochondrial proteomes while inducing extensive remodeling of the lysine succinylome. This latter finding indicates that DC8 is chain shortened to the anaplerotic substrate succinate and that peroxisomal FAO was increased by DC8.ConclusionsDC(8) supplementation protects kidney mitochondria and peroxisomes and increases peroxisomal FAO, thereby protecting against AKI.