Dicarboxylic Acids Protect against CKD

Background: Chronic kidney disease (CKD) affects 30 million people in the US and over 800 million people worldwide. Treatment for end-stage renal failure is largely limited to renal transplant or lifelong dialysis, creating an urgent need for new therapies. We have shown that dicarboxylic acids are protective against acute kidney injury (AKI) in the proximal tubule via hypersuccinylation of mitochondrial and peroxisomal proteins, thereby bolstering peroxisomal fatty acid oxidation over mitochondrial FAO. In this study we aimed to determine whether this mechanism could be leveraged to protect against fibrotic damage due to chronic kidney injury, which we model using Unilateral Ureteral Obstruction (UUO) surgery. Methods: Wild-type male B6/129 mice were procured from Jackson Laboratories and the experimental group fed with an 10% 8-chain dicarboxylic acid (DC8, suberic acid) diet. Both the experimental and the control groups underwent UUO surgery, whereby the ureter of one kidney was obstructed for three days before both kidneys were harvested. Each kidney was split into four pieces as follows – 1. histological and immunohistochemical staining; 2. fatty acid oxidation analysis; 3. succinylome analysis using targeted mass spec; 4. snap-frozen for validation and downstream analysis of fibrosis, as well as peroxisomal and mitochondrial signaling. Results: As previously shown, there was hypersuccinylation in the DC8-treated animals compared to control fed animals. This was accompanied with corresponding upregulation of peroxisomal FAO specifically in the collecting ducts, which was confirmed by targeted mass spec. Supplementation of DC8 showed marked protection in the collecting ducts, with decreased dilation and tubular epithelial shedding compared to controls. There was also a decrease in the dilation of the renal pelvis in DC8 treated animals. Further to this immunohistochemical staining showed a decrease in fibrotic markers in the kidneys of DC8-fed animals Conclusion: Taken together this suggests that DC8 is protective against collecting duct damage and fibrotic changes that occur in CKD. This expands the utilization of DC8 therapy beyond the acute setting and into fibrosis and chronic kidney disease. Funding: NIDDK Support