The Role of Fatty Acid Oxidation in Injured Kidney Tubules

St. Louis Va Medical Center, St. Louis MO

Investigators

Linked publications & trials

Abstract

Background and Innovation: In the Veteran population, acute kidney injury (AKI) increases mortality and risk of chronic kidney disease (CKD), which affects the Veteran population at a higher rate than the general population. Veterans have a high burden of cardiovascular disease, and coronary artery bypass surgery (CABG) can cause ischemic AKI, particularly in those with CKD. The tubules are key targets of AKI, and responses to injury play an important role in determining kidney repair versus fibrosis and progressive loss of function. To meet its high metabolic demands, the proximal tubule uses fatty acid oxidation (FAO) to generate adequate amounts of energy. There is a growing appreciation that tubular FAO is disrupted in kidney injury, but studies directly manipulating fatty acid oxidation proteins are lacking. This proposal uses innovative genetically altered mice that have either CPT1A, the rate-limiting enzyme for mitochondrial FAO, or ACOX1, necessary for peroxisomal FAO, selectively deleted in kidney tubules. The role of these proteins in AKI will be tested using an ischemic model that mimics cardiac surgery and a toxin-based model that also causes human AKI. Preliminary data suggest that blocking CPT1A protects against ischemic AKI, and we will conduct valuable pre- clinical studies on the role of an FDA-approved medication, ranolazine, that has known FAO inhibitory effects, as a preventive treatment for ischemic AKI. Impaired peroxisomal FAO has been implicated in mitochondrial reactive species (mitoROS). We will use the novel PET tracer Galuminox, in the developmental pipeline for use in patients, to investigate the effect of deleting tubular ACOX1 on mitoROS in vivo. We will also leverage the newly formed Metabolism Core and partnerships with Dr. Lodhi, an expert in peroxisomes, and Dr. Finck, an expert in liver metabolism, to further define how FAO is altered in these genetic conditional knockout mice through high resolution respirometry and substrate oxidation assay on tissue ex vivo. Significance and Impact to Veterans Healthcare: Veterans have a high burden of CKD, which predisposes to AKI, and AKI further increases the risk of both death and development of CKD within the Veteran population. The prevalence of diabetes and hypertension, both risk factors for CKD and AKI, are higher in the Veteran population, and the prevalence of coronary artery disease (CAD) is also higher than in the general population. Veterans who undergo CABG to treat CAD are at risk for ischemic AKI, the disease our proposal focuses on and models with ischemia/reperfusion. A gap in our knowledge is whether decreased expression of fatty acid oxidation genes is adaptive or maladaptive. Our data indicate that suppression of CPT1A may be adaptive in the initial response whereas reduction in the peroxisomal FAO enzyme ACOX1 is likely maladaptive. By providing pre-clinical studies on the FDA-approved drug ranolazine, our studies fit the strategic priority to increase the substantial real-world impact of VA research as these studies would have clear translational potential. In addition, there is a clear path to translation that aligns well with the strategic to put VA data to work for Veterans (see below). Path to translation/implementation: The next steps in the path to translation include partnering with Adriana Hung (see letter) to look in the Million Veteran Program (MVP) to see if genetic variants in CPT1A or ACOX1 correlate with susceptibility to and recovery from AKI after CABG. If the genetic variants that are associated with decreased expression of CPT1A correlate with reduced risk of AKI after CABG, this would further support efforts to block CPT1A or FAO to prevent ischemic AKI. Likewise, if our pre-clinical data support ranolazine as a strategy to prevent AKI, the steps to translating this to human studies would be lessened by the fact that ranolazine is already FDA-approved. No studies have genetically altered peroxisomal FAO in the context of AKI, so this model would be helpful in elucidating the role of peroxisomal FAO in AKI and for informing future therapeutic strategies related to peroxisomal FAO.