Impaired fatty acidmetabolism perpetuates lipotoxicity along the transition to chronic kidney injury

Energy metabolism failure in proximal tubule cells (PTC) is a hallmark of chronic kidney injury. We combined 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 ischemia-reperfusion injury (IRI). 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 snRNAseq. 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. 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.