(20S)-Protopanaxatriol (PPT), a biologically active triterpenoid compound derived from Panax ginseng, has traditionally been used in Traditional Chinese Medicine (TCM) for supporting kidney function and maintaining blood pressure balance. This study was designed to investigate the potential protective mechanisms of PPT against renal damage caused by angiotensin II (Ang II). A mouse model of Ang II-induced renal injury was generated using C57BL/6 mice continuously infused with Ang II through osmotic minipumps for four weeks. PPT treatment was started after two weeks of Ang II administration and continued once daily for an additional 14 days. To explore the possible molecular targets of PPT, molecular docking, drug affinity response target stability (DARTS), and cellular thermal shift assay (CETSA) were conducted. Renal function, pathological changes, and alterations in signaling pathways were evaluated through biochemical measurements, histological examination, and Western blot analysis. The results indicated that PPT significantly reduced Ang II-associated renal dysfunction by limiting renal fibrosis and inflammatory responses in mice. Mechanistic investigations revealed that PPT interacted with PTPN1 and suppressed abnormal activation of the AMPK/mTOR signaling pathway, which helped restore autophagy balance in both mouse kidney tissues and Ang II-treated NRK-52E cells. Molecular docking, DARTS, and CETSA analyses further verified PTPN1 as a direct binding target of PPT, supporting its role in PPT-mediated kidney protection. This study provides experimental evidence supporting the traditional application of ginseng in kidney-related disorders and highlights PPT as a promising candidate for managing hypertensive nephropathy through regulation of the PTPN1/AMPK/mTOR signaling axis. Additional clinical studies are required to confirm its therapeutic applicability.
