• Hai-Qin Wang, Hai-Xia Wu, Wei-Qing Shi, Ying Yang, Min Lin, Kai Wang, Chen-Chen Bian, Xiao-Fei An, Tao Wang, and Ming Yan.
• New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, P. R. China.
• Am. J. Chin. Med. 2024 Jan 1; 52 (7): 216121852161-2185.

AbstractDiabetic kidney disease (DKD) is a prominent etiological factor underlying the onset of end-stage kidney disease, which is characterized by the presence of microalbuminuria. Recent studies have found that high glucose can induce mitochondrial dysfunction and ferroptosis in podocytes, leading to renal impairment and proteinuria. Triptolide was extracted from traditional Chinese medicine Tripterygium wilfordii Hook F., which has anti-inflammatory, anti-oxidant, and podocyte protective activities. Multiple studies have shown that triptolide can ameliorate proteinuria in DKD. However, the specific mechanisms remain unclear. This study investigates whether triptolide can reverse proteinuria in DKD by inhibiting ferroptosis in db/db mice and its specific protective mechanisms. The results demonstrate that triptolide could preserve podocytes and reduce proteinuria in db/db mice via inhibiting ferroptosis. In vivo and in vitro, the expression of glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH-1), and the cystine/glutamate reverse antiporter solute carrier family 7 member 11 (SLC7A11) were increased, and the production of transferrin receptor 1 (TFR-1) was decreased by triptolide. Moreover, triptolide suppressed oxidative stress and mitochondria dysfunction. Additionally, triptolide up-regulated the expression of NFE2-related factor 2 (Nrf2) and change the expression of its downstream targets related to ferroptosis. Furthermore, the podocyte actin cytoskeleton was stabilized by triptolide, and the transition from slit diaphragm (SD) to tight junction (TJ), which is a pivotal character of filtration barrier damage, was attenuated by triptolide. In conclusion, our results suggest that triptolide could stabilize the glomerular podocyte cytoskeleton and attenuate renal SD-TJ transition in DKD by upregulating Nrf2 and thereby inhibiting ferroptosis.

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