LIGHT deficiency attenuates acute kidney disease development in an in vivo experimental renal ischemia and reperfusion injury model.

Ischemia-reperfusion (I/R), a leading risk factor of acute kidney injury (AKI), is associated with high mortality and risk of progression to chronic kidney disease. However, the molecular mechanism of I/R-AKI remains not fully understood, which hinders its efficient clinical treatment. In this study, we observed that LIGHT deficiency remarkably attenuated I/R-AKI, as evidenced by rescued renal function, ameliorated tubular cell apoptosis, and alleviated inflammatory responses. Consistently, blocking LIGHT signaling with its soluble receptor fusion proteins (HVEM-IgG-Fc or LTβR-IgG-Fc) improved I/R renal dysfunction. RNA-sequencing and corresponding results indicated that LIGHT promoted oxidative stress and inflammation triggered by ischemic injury. Moreover, LIGHT signaling augmented ischemic stress-induced mitochondrial dysfunction characterized by an imbalance in mitochondrial fission and fusion, decreased mtDNA copies, impaired mitophagy, and increased mitochondrial membrane potential (ΔΨm). Mechanistically, LIGHT promoted mitochondrial fission by enhancing Drp1 phosphorylation (Ser616) and its translocation to the mitochondria. In conclusion, these results suggest that LIGHT-HVEM/LTβR signaling is critical for the I/R-AKI pathogenesis and it is further confirmed to be related to the increase in I/R-induced oxidative stress and mitochondria dysfunction, which may be the underlying mechanism of LIGHT signaling-mediated I/R-AKI.