Dicarboxylic Acid Dietary Supplementation Protects against AKI

Abstract

Introduction: 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. Methods and Results: Mice were fed with either a control diet or diet enriched with dicarboxylic acids, which are peroxisome-specific FAO substrates, then subjected to either IRI-AKI or cisplatin-AKI models. Biochemical, histologic, genetic, and proteomic analyses were performed. Both octanedioc acid (DC8) and dodecanedioc 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. o Conclusion: DC8 supplementation protects kidney mitochondria and peroxisomes and increases peroxisomal FAO, thereby protecting against AKI.

Dietary dicarboxylic acids provide a nonstorable alternative fat source that protects mice against obesity

“…This is supported by reduced blood lactate in DC 12 -fed mice after treadmill running ( Figure 2I ). Reduced oxygen demand while catabolizing DCAs may also explain our previous observation that DCAs protect against ischemic kidney injury ( 64 ). Additional studies are underway to optimize the dosing and formulation for oral DC 12 .…”