Artemether Attenuates High Glucose-Induced Inflammation and Fibrogenesis in Renal Tubular Epithelial Cells by Modulating the TGF-β/Smad Pathway Via PPARγ Activation.

Artemether (Art) is a derivative of artemisinin, originally sourced from traditional Chinese herbal medicine, with improved bioavailability, and is widely used for malaria treatment. Recently, its potential effects on diabetic complications, particularly diabetic kidney disease (DKD), have attracted increasing attention. This study aimed to evaluate the therapeutic effects of Art on DKD and to explore the underlying mechanisms. Specifically, we investigated the protective role of Art against high glucose (HG)-induced inflammatory biomarkers (transforming growth factor-β1 [TGF-β1], tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β], and interleukin-6 [IL-6]) and fibrosis in human renal proximal tubular epithelial (HK-2) cells, focusing on the involvement of peroxisome proliferator-activated receptor gamma (PPARγ) in DKD. To mimic diabetic conditions, HK-2 cells were exposed to HG (30 mM) to induce inflammation and fibrosis. The therapeutic effects of Art (100 and 200 μm) were assessed by immunofluorescence, real-time RT-PCR, and Western blot analyses. Our results demonstrated that Art effectively reversed the HG-induced upregulation of inflammatory and fibrogenic markers in HK-2 cells (∗p < 0.05, ∗∗p < 0.001, and ⁣(##) p < 0.001). Additionally, Art pretreatment restored the HG-suppressed expression of PPARγ (∗p < 0.05 and ⁣(##) p < 0.001), suggesting that Art exerts its antifibrotic effects by modulating PPARγ and inhibiting the TGF-β/Smad pathway. This hypothesis was further supported by siRNA-mediated knockdown of PPARγ, which significantly diminished Art's antifibrotic effects (∗p < 0.05, ∗∗p < 0.001, and ⁣(##) p < 0.001). In conclusion, our study indicates that Art protects renal tubular epithelial cells by partially modulating PPARγ-dependent inhibition of the TGF-β/Smad pathway, thereby mitigating HG-induced inflammation and fibrosis. These findings suggest that Art holds promising therapeutic potential for DKD treatment.