Artemether prevents renal proximal tubules enlargement in high‑fat diet induced obese mice

Enlarged kidney size is a common pathological manifestation in obesity, yet no effective therapeutic strategies currently exist to prevent this process. The present study aimed to investigate the effects of artemether, an artemisinin‑based drug, on kidney weight and renal proximal tubules (PTs) enlargement in obese mice. High‑fat diet (HFD)‑induced obese mice were established and treated with artemether. Obesity phenotype, kidney weight and PTs pathology were evaluated. Molecular mechanisms were explored in vitro using TKPTS cells. The results demonstrated that artemether markedly reduced kidney weight and attenuated PTs enlargement in HFD mice independent of body weight changes. In HFD mice, PTs exhibited over‑proliferation, excessive lipid droplets deposition and metabolic dysfunction. Artemether inhibited PTs hyperproliferation, reduced key glycolytic enzymes, upregulated mitochondrial pyruvate carrier (MPC) 1, MPC2 and isocitrate dehydrogenase subunit β in kidney. However, the renal triglyceride/cholesterol levels and mitochondrial β‑oxidation related proteins were not affected by artemether. In vitro, artemether mitigated fatty acids‑induced decline in mitochondrial membrane potential, modulated mitochondrial respiration and disturbed oxidative phosphorylation. Furthermore, although artemether decreased glycolytic gene transcription and glycolytic reserve, it unexpectedly increased lactate excretion. Additionally, artemether enhanced fatty acid oxidation, likely increased pyruvate oxidation and tricarboxylic acid cycle rate, and suppressed fatty acids activated TGF‑β1 signaling. Collectively, these findings suggested that artemether reduces kidney weight and prevents PTs enlargement in HFD mice, likely through modulating mitochondrial respiration and remodeling energy metabolism.