Atorvastatin Attenuates Vancomycin-Induced Nephrotoxicity via PPARα-Associated Regulation of SLC Transporters

Kexin Lin,1,* Tingyu Li,2,* Xiaorui Kong,1 Tong Li,1 Yawen Zuo,1 Deshi Dong,1 Shilei Yang,1 Yanna Zhu1 1Department of Pharmacy, The First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China; 2Department of Pharmaceutics, Dalian Women and Children’s Medical Group, Dalian, Liaoning, 116012, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shilei Yang, Email [email protected] Yanna Zhu, Email [email protected]: Vancomycin (VCM) is a first-line antibiotic for severe infections, but its clinical utility is limited by nephrotoxicity. Atorvastatin (ATO), a widely used lipid-lowering agent, has shown renoprotective potential. However, whether ATO mitigates vancomycin-induced nephrotoxicity (VIN) remains unclear.Methods: We investigated the effects of ATO on VIN using male C57BL/6 mice and HK-2 cells. Renal function, histopathology, inflammation, oxidative stress, and apoptosis were assessed. Transcriptome sequencing of renal tissue was performed to explore underlying mechanisms.Results: In vivo, ATO significantly improved VCM-induced renal dysfunction and renal pathological damage in mice. It significantly suppressed the release of inflammatory cytokines, enhanced renal antioxidant capacity, and reduced renal cell apoptosis. In vitro, ATO significantly increased HK-2 cell viability while reducing inflammation, reactive oxygen species (ROS) production, and renal cell apoptosis. Transcriptomic analysis revealed that ATO modulated peroxisome proliferator-activated receptor α (PPARα) signaling activity, which was accompanied by upregulated expression of solute carrier (SLC) transporters.Conclusion: This preclinical study demonstrates for the first time that ATO attenuates VIN by a PPARα-associated signaling pathway that orchestrates the upregulation of SLC transporters (including OAT1, OAT3, OCT2, and MATE1) to promote the excretion of endogenous toxins, with concomitant integrated protective effects against inflammation, oxidative stress, and apoptosis. These findings identify a novel mechanism and potential therapeutic strategy for VIN.Keywords: atorvastatin, vancomycin, nephrotoxicity, PPARα, SLC transporters