Autotaxin inhibition mitigates chronic kidney disease by reducing renal tubular lysosome–mitochondria stress and suppressing fibroblast activation

Background: Autotaxin (ATX) catalyzes lysophosphatidic acid (LPA) production and has been implicated in fibrotic diseases. However, its role in chronic kidney disease (CKD), particularly its spatial distribution and association with tubular injury, and its contribution to cellular remodeling remains unclear. This study investigated the therapeutic effects and potential mechanisms of autotaxin inhibition (ATXi) in experimental CKD. Methods: ATX expression and cell type-specific Enpp2 expression were evaluated in CKD mouse models induced by folic acid (FA) or an adenine diet. In a separate intervention study, FA-induced CKD mice were treated with ATXi or vehicle. Renal function, fibrosis, tubular injury, lipid accumulation, and mitochondrial and lysosomal alterations were assessed. In vitro, NRK-49F fibroblasts were treated with transforming growth factor beta (TGF-β) with or without ATXi. Results: ATX expression was increased in CKD kidneys and was predominantly localized to the tubulointerstitium. ATXi treatment significantly attenuated blood urea nitrogen elevation and tended to reduce cystatin C levels, along with improving tubular injury and interstitial fibrosis, collagen deposition and alpha-smooth muscle actin expression. Renal lipid accumulation and increased LPA receptor mRNA expression observed in CKD were also reduced following ATXi treatment. In addition, ATXi ameliorated tubular mitochondrial structural damage and lysosomal stress. Furthermore, ATXi suppressed TGF-β-induced fibroblast activation and proliferation in vitro. Conclusion: Pharmacologic inhibition of ATX attenuated CKD, accompanied by improvements in mitochondrial structural abnormalities, modulation of lysosome-associated responses, and suppression of fibroblast activation, thereby reducing tubular injury and renal fibrosis. These findings support a pathogenic role of the ATX-LPA axis in CKD and highlight ATXi as a potential therapeutic target.