#5790 IMPAIRED FATTY ACID METABOLISM PERPETUATES LIPOTOXICITY ALONG THE TRANSITION TO CHRONIC KIDNEY INJURY

Abstract

Abstract Background and Aims Understanding the cell-intrinsic mechanisms contributing to the maintenance of a dysfunctional cellular state in chronic kidney disease (CKD) and identifying therapeutic targets are research priorities in renal medicine. A key contributor to chronic kidney histological damage is acute kidney injury, especially ischemia-reperfusion injury (IRI). Persistent cell-extrinsic perturbations generated upon IRI, for example hypoxia, impair the energetic metabolism of Proximal Tubular Cells (PTC) participating in the process of transition from acute to chronic kidney injury. Here, we propose to investigate the PTC intrinsic factors involved in the perpetuation of an impaired cellular state which contribute to CKD progression Method We combined single nucleus transcriptomic, metabolomic and lipidomic approaches in experimental models and patient cohorts to investigate the molecular bases of the progression to chronic kidney allograft injury initiated by IRI. Results The urinary metabolome of kidney transplant recipients with chronic allograft injury and who experienced severe IRI was significantly enriched with long chain fatty acids (FA). We identified a renal FA-related gene signature with low levels of Cpt2 and Acsm5 and high levels of Acsl4 and Acsm5 associated with IRI, transition to chronic injury, and established CKD in mouse models and kidney transplant recipients. The findings were consistent with the presence of Cpt2-, Acsl4+, Acsl5+, Acsm5- PTC failing to recover from IRI as identified by single nucleus RNA sequencing. In vitro experiments indicated that endoplasmic reticulum (ER) stress contributes to CPT2 repression, which, in turn, promotes lipids accumulation, drives profibrogenic epithelial phenotypic changes, and activates the unfolded protein response. Conclusion ER stress through CPT2 inhibition and lipid accumulation, engages an auto-amplification loop leading to lipotoxicity and self-sustained cellular stress. Thus, IRI imprints a persistent FA metabolism disturbance in the proximal tubule sustaining the progression to chronic kidney allograft injury.