ABSTRACT: Fatty acid binding protein 5 (FABP5) belongs to the FABP family of intracellular fatty acid transporters. Under physiological conditions, this family plays a crucial role in handling lipids taken up from the environment, facilitating their transport to sites of storage and subsequently to membranes, mitochondria, and nuclei. Therefore, FABPs contribute to membrane biogenesis, lipid-mediated signalling, lipogenesis, lipolysis, and lipid degradation. In the kidney, dysregulated expression of certain FABP members has been associated with the development of acute kidney injury (AKI), and they are thus proposed as biomarkers of this condition. However, the specific role of FABP5 remains unaddressed. Functional assays to investigate the role of FABP5 were carried out using cellular and animal loss-of-function models. In vitro, FABP5 activity was pharmacologically inhibited, after which lipid storage, degradation, and cellular stress events leading to cell death were assessed. In vivo, the role of FABP5 was evaluated by comparing FABP5-deficient mice subjected to folic acid–induced AKI (FA-AKI) with wild-type mice, as well as in wild-type mice treated with a pharmacological FABP5 inhibitor. The involvement of FABP5 in FA-AKI was first explored through renal transcriptomic analysis and subsequently validated by biochemical assessment of renal function and injury markers. FABP5 expression was found to be significantly reduced in the FA-AKI model. Inhibition of FABP5 activity in renal tubular cells led to increased cellular stress, characterised by depletion of lipid droplets, impaired fatty acid delivery to mitochondria, reduced ATP levels, oxidative stress, mitochondrial loss, and cell death. Consistently, both genetic deletion and pharmacological inhibition of FABP5 aggravated the initial phase of the disease. These results demonstrate that FABP5 instability represents an important maladaptive mechanism during AKI. Therefore, preservation of FABP5 may confer resilience to AKI.
