2. Academic Validation
  3. Shen-Shuai-II-Recipe suppresses hypoxia-induced oxidative stress and ferroptosis via Nrf2 activation to ameliorate renal fibrosis in chronic kidney disease

Shen-Shuai-II-Recipe suppresses hypoxia-induced oxidative stress and ferroptosis via Nrf2 activation to ameliorate renal fibrosis in chronic kidney disease

  • J Ethnopharmacol. 2025 Oct 24:356:120783. doi: 10.1016/j.jep.2025.120783.
Yizeng Xu 1,  Meng Wang 2,  Lingchen Wang 2,  Xinyue Zhang 2,  Gangyi Chen 3,  Chen Wang 4
Affiliations

Affiliations

  • 1 Department of Nephrology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou, China. Electronic address: [email protected].
  • 2 Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, China; TCM Institute of Kidney Disease, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 3 Department of Nephrology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou, China.
  • 4 Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, China; TCM Institute of Kidney Disease, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: [email protected].
PMID: 41139039 DOI: 10.1016/j.jep.2025.120783
Abstract

Ethnopharmacological relevance: Shen-Shuai-II-Recipe (SSR), a clinically effective Chinese herbal formula for chronic kidney disease (CKD) management, has shown potential anti-hypoxia and anti-fibrosis properties in rat models of CKD. However, the underlying molecular mechanisms of its renoprotection warrant further elucidation.

Aim of the study: This study investigated the mechanisms of SSR's renoprotective actions under chronic hypoxia condition of CKD.

Materials and methods: In vivo, 5/6 renal ablation/infarction (A/I) rat models of CKD were established and administered with SSR or losartan for eight weeks. In vitro, NRK-52E cells underwent chronic hypoxia induction and were treated with SSR-medicated serum and (or) Nrf2 inhibitor (ML385). Renal hypoxia, oxidative stress, Ferroptosis, and fibrosis were assessed via blood oxygenation level-dependent MRI, histopathology, colorimetry, immunoblotting, and fluorometry.

Results: SSR significantly suppressed oxidative stress and Ferroptosis in 5/6 (A/I) kidneys, concomitant with alleviated hypoxia and fibrosis, which was associated with the up-regulated expression of Nrf2 protein. Hypoxic NRK-52E cells exhibited time-dependent increases in fibrosis and hypoxia-related proteins and suppression of the Nrf2 pathway. Furthermore, SSR significantly improved antioxidant capacity, attenuated lipid peroxidation and fibrosis in chronic hypoxia induced NRK-52E cells by activating the Keap1-Nrf2/xCT/GPX4 axis, while the effect was diminished by Nrf2 inhibition.

Conclusions: SSR inhibits hypoxia-induced oxidative stress and Ferroptosis to ameliorate renal fibrosis in CKD via Nrf2 activation.

Keywords

Chronic kidney disease; Ferroptosis; Nrf2; Oxidative stress; Renal hypoxia; Traditional Chinese medicine.

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