The kidney possesses a highly complex reabsorption function, with tubular epithelial cells (TECs) being the primary functional units. The TECs mainly rely on fatty acid oxidation (FAO) for energy supply. FAO is hindered during ischemia-reperfusion (I/R)-induced acute kidney injury (AKI), leading to impairments in oxidative phosphorylation. The energy supply to renal TECs then shifts from FAO to glycolysis. Impaired fatty acid uptake and oxidation, coupled with sustained increases in glycolysis, can lead to irreversible damage or failure of TEC regeneration. This causes TEC atrophy, inadequate adaptive repair, progression to chronic kidney disease (CKD), and fibrosis. Irisin, a protein secreted by skeletal muscle, is a factor in regulating energy homeostasis. The beneficial effects of exercise on diabetic kidney disease are primarily mediated through its actions. In vitro and in vivo models of our experiments show that irisin can correct the energy metabolic disorders of renal TECs following I/R, increase FAO, reduce glycolysis, and improve I/R-induced AKI. Target points of irisin were explored to elucidate the specific mechanisms of action. We found that the integrin αVβ5 receptor, a target of irisin, is also expressed in TECs and is upregulated following hypoxia/reoxygenation (H/R). Bioinformatics showed significant differences in the AMPK (PRKAA2) and mTOR genes between AKI and normal mice and identified protein interaction among FNDC5/irisin, AMPK, and mTOR. Examination of the effects of irisin on AMPK, mTOR, and the mTOR downstream target HIF-1α showed that pre-treatment with irisin increased the phosphorylation of AMPK in H/R-treated HK-2 cells while simultaneously suppressing mTOR phosphorylation and reducing HIF-1α expression. However, pretreatment with an anti-integrin αVβ5 antibody inhibited the regulatory effects of irisin on AMPK/mTOR phosphorylation and HIF-1α protein levels in H/R-treated HK-2 cells. Given their recognized regulatory roles in energy metabolism, particularly in FAO and glycolysis, our experiments investigating the effects of AMPK and mTOR modulation demonstrated that suppression of AMPK or stimulation of mTOR impeded Irisin's ability to modulate these processes in response to I/R, as well as its ameliorative impact on AKI. Therefore, we concluded that irisin exerts its beneficial effects by binding to the integrin αVβ5 receptor on the membrane of renal TECs, thereby modulating the AMPK/mTOR pathway to improve FAO and reduce glycolysis, ultimately ameliorating I/R-induced AKI, with HIF-1α also participating in this regulatory process. (Graphical Abstract).
